Novel 1,2,4  Oxadiazole Compounds and Methods of Use Thereof

ABSTRACT

The invention relates to 1,2,4 oxadiazole compounds and analogs thereof, represented by formula (II), and compositions and methods of use thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S. patentapplication Ser. No. 11/953,625, filed Dec. 10, 2007, which claimspriority from U.S. Patent Application Ser. No. 60/999,761, filed Apr.12, 2007 and U.S. Patent Application 60/874,609, filed Dec. 12, 2006,each of which is herein incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Technical Field

The invention relates to novel compounds and compositions comprisingoxadiazole derivatives, and methods of using the same.

2. Description of Related Technology

The endogenous cholinergic neurotransmitter, acetylcholine (ACh), exertsits biological effect via two types of cholinergic receptors, themuscarinic acetylcholine receptors (mAChR) and the nicotinicacetylcholine receptors (nAChR). nAChRs are pentameric assemblies ofsubunits surrounding a central pore that gates the flux of Na⁺, K⁺ andCa²⁺ ions. At least 16 subunit proteins, i.e. α2-α10, β1-β10, γ, δ andε, have been identified in neuronal tissues. These subunits provide fora great variety of homomeric and heteromeric combinations that accountfor the diverse receptor subtypes. For example, functional neuronalnAChR or neuronal nicotinic receptor (NNR) assemblies can be homomeric,comprising α7 or α8 or α9 subunits, or heteromeric, usually with atleast one subunit from the α group (α2, α3, α4, α6) and the remainderfrom the β group (β2, β4). In the central nervous system,α4β2-containing NNR and α7-containing NNR subtypes are the mostwidespread and mediate synaptic and, possibly, paracrine functions.These NNRs are expressed at high levels in areas involved with learningand memory, and play key roles in modulating neurotransmission in theseregions. Reduced cholinergic activity and dysregulation of NNRs havebeen correlated with disease states involving cognitive deficits,progressive dementia, and epilepsy. Accordingly, these NNRs areimplicated in a range of physiological and patho-physiological functionsrelated to cognitive function, learning and memory, reward, motorcontrol, arousal and analgesia (reviewed in Gopalakrishnan, M. et al.,Ion channels—Ligand-gated. Comprehensive Medicinal Chemistry II, Editedby Triggle D. J. et al., Major Reference Works, Elsevier. Unit 2.22, pp877-918, 2006).

Neuronal nicotinic receptors, especially α4β2 neuronal nicotinicacetylcholine receptors (nAChRs) have been targeted for pain and variouscentral nervous system diseases. Antisense knockdown of the α4 subunitwas found to decrease the analgesic effect of agonists (Bitner R S, etal., Brain Res. 871:66-74, 2000). Reduced antinociceptive responses tonicotine also is seen in α4 gene knockout animals (Marubio L M, et al.,Nature 398:805-810, 1999). Both α4 and β2 nAChRs are responsible formediating nicotinic analgesia at supraspinal responses and spinal sites(Decker, M W, et al, Curr Top Med Chem., 4: 369-384, 2004).Antinociceptive effects through α4β2 nAChRs are generally attributed tostimulation of brainstem monoaminergic transmission, particularly in theraphe (Cucchiaro G, et al., J Pharmacol Exp Ther. 313:389-394, 2005).However, α4β2 stimulation of GABAergic and glycinergic inhibitorytransmission in the spinal cord also may contribute (Rashid M H, et al.,Pain 125:125-135, 2006).

Central α3* nAChRs may contribute to nicotinic analgesia (Khan I M, etal., J Neurocytol. 33:543-556, 2004), but α3β4 ligands are of littleinterest because of likely autonomic side effects. Indeed, the goal hasbeen to avoid α3* neuronal nicotinic receptor (NNR), as thedose-limiting emetic liability of nonselective compounds has beenattributed to activation of α3 containing nAChRs. α3* nAChRs areexpressed in the enteric nervous system as well as in other componentsof the peripheral and central nervous systems. Area postrema and nucleustractus solitarius are brainstem nuclei thought to be involved in nauseaand emesis. α3* nAChRs in the dorsal motor nucleus of the vagus and innucleus tractus solitarius have been implicated in gastric and bloodpressure responses to nicotine injected locally (Ferreira M, et al J.Pharmacol. Exp. Ther., 294:230-238, 2000).

Compounds with varying degrees of selectivity for α4β2 nAChRs over othernicotinic subtypes (α3, α7, α1-containing) have been discovered over theyears. For example, ABT-594 (referred to as Compound A in thisapplication) was efficacious across a number of rodent models ofnociception including acute thermal, chemogenic, neuropathic, andvisceral pain (Decker M W, et al., Expert Opinion on InvestigationalDrugs, 10:1819-1830, 2001). Available data suggest that ligands withselectivity for the α4β2 nAChRs over α3β4 efficacy is preferred for lowadverse event profiles. In theory, the therapeutic index could beexpanded by (a) reducing α3β4 activity or (b) increasing α4β2 efficacywithout increasing α3β4 activity. The latter may be achieved by an α4β2selective positive allosteric modulator (PAM) either alone or incombination with exogenous α4β2 agonist. Positive allosteric modulatorscan potentiate effects by enhancing the efficacy and or potency ofagonists. Accordingly, an α4β2 selective positive allosteric modulatorcan selectively enhance effects at the preferred α4β2 nAChRs over othernAChR subtypes.

Initially known positive allosteric modulators of the α4β2 nAChRs havebeen nonselective and not very potent. For example, nefiracetam has beenreported to potentiate α4β2 nAChR responses (Narahashi T, et al., Biol.Pharm. Bull., 27:1701-1706, 2004). More recently, subtype selective PAMshave been disclosed. Compounds like3-(3-pyridin-3-yl-1,2,4-oxadiazol-5-yl)benzonitrile and others have beendescribed with robust α4β2 PAM effects with little modulatory activityat other subtypes such as α3β4 (e.g., see WO 2006/114400, published Nov.2, 2006).

Pain is an unmet medical need and the methods and possibilities fortreatments of such indications are insufficient. Although continuedefforts are being made to treat pain using nAChR agonists, robustefficacy in pain may be limited by the range of side effects associatedwith their use, albeit to differing degrees. In light of thesignificance of chronic pain and the limitations in their treatment, itwould be beneficial to identify new methods of treating such disorders,particularly in a manner that reduces adverse ganglionic effects such asat the gastrointestinal systems (e.g. emesis). It would be particularlybeneficial to identify compounds and compositions that offer anopportunity to wide the therapeutic window of nicotinic (nAChR) agonistsin pain. Enhanced efficacy with nAChR ligands for the treatment of othercentral nervous system diseases such as cognitive and attention deficitsis also desirable.

SUMMARY OF THE INVENTION

The invention relates to oxadiazole compounds, compositions comprisingsuch compounds, and methods of using such compounds and compositions.

In one aspect, the invention is directed to compounds of formula II

wherein Ar¹ and Ar² are independently optionally substituted aryl orheteroaryl, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention relates to pharmaceutical compositionscomprising compounds of the invention. Such compositions can beadministered in accordance with a method of the invention, typically aspart of a therapeutic regimen for treatment or prevention of conditionsand disorders related to nAChR activity, and more particularly α4β2nAChR positive allosteric modulator activity.

Yet another aspect of the invention relates to a method of modulatingα4β2 nAChR positive allosteric modulator activity. The method is usefulfor treating, preventing or both treating and preventing conditions anddisorders related to α4β2 nAChR positive allosteric modulator activity,particularly in mammals.

One embodiment of this invention provides compositions that are usefulfor treatment of diseases or disorders related to the nicotinicacetylcholine receptor (nAChR) with enhanced efficacy and less sideeffects than nicotinic agents alone.

Another embodiment of the invention relates to methods and compositionswherein the efficacy of a nicotinic (nAChR) agent is enhanced byco-dosing a nicotinic ligand with a positive allosteric modulator (PAM)of nAChR subtype α4β2. Another embodiment of the invention relates tomethods and compositions for treatment of individuals withnAChR-mediated diseases or disorders, and particularly for pain or CNSdisorders, which involves a combination of a nicotinic ligand with anα4β2 positive allosteric modulator.

In one embodiment, the invention relates to methods and compositionscomprising (i) a nicotinic acetylcholine receptor ligand; and (ii) anicotinic acetylcholine receptor subtype α4β2 selective positiveallosteric modulator, in admixture with at least one pharmaceuticallyacceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B depict responses of a representative nicotinicacetylcholine receptor ligand,5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine (Compound A) in theabsence and presence of a nicotinic acetylcholine receptor subtype α4β2positive allosteric modulator,3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (PAM, Compound 1),at human α4β2 or α3β4 nicotinic acetylcholine receptor subtypesexpressed in HEK-293 cells. The data demonstrate a leftward shift inpotency (EC₅₀ value) at α4β2, but not α3β4, nAChRs.

FIGS. 2A and 2B depict responses of another representative nicotinicacetylcholine receptor ligand, (3R)-1-pyridin-3-ylpyrrolidin-3-amine(Compound B), in the absence and presence of an α4β2 positive allostericmodulator, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (PAM,Compound 1), at human α4β2 or α3β4 nicotinic receptor subtypes expressedin HEK-293 cells. Again, the data demonstrate a leftward shift inpotency (EC₅₀ value) of the nAChR agonist at α4β2, but not α3β4 nAChRs.

FIGS. 3A and 3B graphically represent the effect of α4β2 positiveallosteric modulator in enhancing the effect of a nAChR partial agonist,such as 2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine (Compound C, alsoknown as ABT-089; Reuter, L. E., et al., CNS Drug Rev., 10 (2), 167-182,2004). Compound C alone does not evoke a calcium response, but whenco-applied with the PAM,3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1),evoked robust responses at α4β2 nAChRs (FIG. 3A), but not at α3β4 nAChRs(FIG. 3B). Compound C is a representative of other nicotinic partialagonists.

FIGS. 4A and 4B graphically represent the effect of an α4β2 positiveallosteric modulator in enhancing the effect of another nAChR partialagonist (1S,5S)-3-(3,6-diaza-bicyclo[3.2.0]hept-3-yl)-quinoline(Compound D; α4β2 [³H]cytisine K_(i)=6 nM)). Compound D alone does notevoke a response, but when co-applied with the PAM,3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1),evoked robust responses at α4β2 nAChRs (FIG. 4A), but not at α3β4 nAChRs(FIG. 4B). Compound D is a representative of other nicotinic partialagonists.

FIG. 5 shows correlation of potencies for activation of α4β2 nAChRs byvarious nicotinic acetylcholine receptor ligands in the presence andabsence of an α4β2 PAM,3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1). Ingeneral, these nicotinic ligands are found to be more potent inactivating α4β2 nAChRs in the presence of α4β2 PAM (Compound 1).

FIG. 6A graphically represents the effect of an α4β2 PAM,3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1), onenhancing the efficacy by 5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine(Compound A) in reversing neuropathic pain.

FIG. 6B graphically represents the dose dependent effect of an α4β2 PAM,3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1), onenhancing the neuropathic pain efficacy of5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine (Compound A). Anineffective dose of Compound A (1 nmol/kg) demonstrates effect whencombined with various doses of α4β2 PAM (Compound 1).

FIG. 7A shows dose-dependent effects in neuropathic pain of5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine (Compound A) alone, α4β2PAM, 3-(3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1),alone and a combination of Compound 1 (3.5 μmol/kg) with various dosesof Compound A. An α4β2 PAM (Compound 1) alone is ineffective. However,in the presence of Compound 1 the dose response curve of Compound A inthe Chung model of neuropathic pain shifts to the left.

FIG. 7B shows the effects on emesis in ferrets. The effects of5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine (Compound A) alone, α4β2PAM, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1),alone and a combination of Compound 1 (3.5 μmol/kg) with various dosesof Compound A are shown. An α4β2 PAM (Compound 1) alone does not causeemesis, and does not shift the dose response curve of Compound A in theferret model of emesis.

FIGS. 8A and 8B show plasma level analysis in models of neuropathic painand emesis. The efficacy of Compound A is shifted left-ward as shown inFIG. 8A, but no shift in effects on emesis are shown in FIG. 8B. Themaximal efficacy of Compound A can be realized in neuropathic painwithout incidence of emesis, in presence of α4β2 PAM,3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1). Thedata demonstrates that the therapeutic window of α4β2 nAChR agonists iswider in the presence of α4β2 PAM.

FIG. 9 shows the efficacy of a partial agonist, Compound D, in thepresence and absence of α4β2 PAM,3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1). Inthe example illustrated, Compound D when administered alone isineffective in relieving pain. When co-dosed with α4β2 PAM (Compound 1),Compound D demonstrates effect, and the data demonstrate that Compound Dprovides significant relief of neuropathic pain in rats.

FIG. 10 is a graphical representation of specific binding to receptorsites in human brain membranes (fmoles per mg protein) as a function ofthe concentration of a radioligand[³H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile ([³H]-POB,nM).

DETAILED DESCRIPTION OF THE INVENTION Definition of Terms

For a variable that occurs more than one time in any substituent or inthe compound of the invention or any other formulae herein, itsdefinition at each occurrence is independent of its definition at everyother occurrence. Combinations of substituents are permissible only ifsuch combinations result in stable compounds.

As used throughout this specification and the appended claims, thedesignation C_(x)-C_(y), wherein x and y are integers from 1 to 10 referto a range of carbon atoms in the hydrocarbon portion of the group whichit modifies, for example, the designation “C₁-C₆ haloalkyl” refers to atleast one halogen appended to the parent molecular moiety through analkyl group having from 1 to 6 carbon atoms.

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “acyl hydrazide”, as used herein, means a —C(O)NHNH₂ group.

The term “alkenyl”, as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy”, as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkoxy”, as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through anotheralkoxy group, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy,2-methoxyethoxy, and methoxymethoxy.

The term “alkoxyalkoxyalkyl”, as used herein, means an alkoxyalkoxygroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofalkoxyalkoxyalkyl include, but are not limited to,tert-butoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy)methyl,and 2-(2-methoxyethoxy)ethyl.

The term “alkoxyalkyl”, as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of alkoxyalkylinclude, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl,2-methoxyethyl, and methoxymethyl.

The term “alkoxycarbonyl”, as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxycarbonylalkyl”, as used herein, means an alkoxycarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofalkoxycarbonylalkyl include, but are not limited to,3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and2-tert-butoxycarbonylethyl.

The term “alkoxycarbonylamino”, as used herein, means an alkoxycarbonylgroup, as defined herein, appended to the parent molecular moietythrough an amino group, as defined herein. Representative examples ofalkoxycarbonyamino include, but are not limited to,t-butoxycarbonylamino and methoxycarbonylamino.

The term “alkoxycarbonylaminoalkyl”, as used herein, means analkoxycarbonylamino group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.Representative examples of alkoxycarbonyaminoalkyl include, but are notlimited to, t-butoxycarbonylaminomethyl and methoxycarbonylaminopropyl.

The term “alkoxysulfonyl”, as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkoxysulfonyl include, but are not limited to, methoxysulfonyl,ethoxysulfonyl and propoxysulfonyl.

The term “alkyl”, as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylamino”, as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an amino group,as defined herein. Representative examples of alkylamino include, butare not limited to, methylamino, ethylamino, and t-butylamino.

The term “alkylcarbonyl”, as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylcarbonylalkyl”, as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofalkylcarbonylalkyl include, but are not limited to, 2-oxopropyl,3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.

The term “alkylcarbonyloxy”, as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom. Representative examples of alkylcarbonyloxyinclude, but are not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy.

The term “alkylcarbonyloxylalkyl”, as used herein, means analkylcarbonyloxy group, as defined herein, appended to the parentmolecular moiety through an alkyl group.

The term “alkylene”, as used herein, means a divalent group derived froma straight or branched chain hydrocarbon of from 1 to 10 carbon atoms.Representative examples of alkylene include, but are not limited to,—CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and—CH₂CH(CH₃)CH₂—.

The term “alkylsulfinyl”, as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfinyl group, as defined herein. Representative examples ofalkylsulfinyl include, but are not limited to, methylsulfinyl andethylsulfinyl.

The term “alkylsulfinylalkyl”, as used herein, means an alkylsulfinylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofalkylsulfinylalkyl include, but are not limited to, methylsulfinylmethyland ethylsulfinylmethyl.

The term “alkylsulfonyl”, as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “alkylsulfonylalkyl”, as used herein, means an alkylsulfonylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined

The term “alkylthio”, as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of alkylthio include, but are not limited,methylthio, ethylthio, tert-butylthio, and hexylthio.

The term “alkylthioalkyl”, as used herein, means an alkylthio group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of alkylthioalkylinclude, but are not limited, methylthiomethyl and 2-(ethylthio)ethyl.

The term “alkynyl”, as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “amino”, as used herein, means a —NH₂ group.

The term “aminoalkyl”, as used herein, means at least one amino group,as defined herein, is appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of hydroxyalkylinclude, but are not limited to, aminomethyl, 2-aminoethyl,3-aminopropyl, and 2-ethyl-4-aminoheptyl.

The term “amido”, as used herein, means an amino (H₂N—), alkylamino(alkylN(H)—), dialkylamino (alkyl₂N—), arylamino (arylN(H)—),arylalkylamino (arylalkylN(H)—) or another substituted amine groupappended to the parent molecular moiety through a carbonyl group, asdefined herein. Representative examples of amido include, but are notlimited to, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl,and ethylmethylaminocarbonyl.

The term “aryl,” as used herein, means phenyl, a bicyclic aryl or atricyclic aryl. The bicyclic aryl is naphthyl, a phenyl fused to acycloalkyl, or a phenyl fused to a cycloalkenyl. Representative examplesof the bicyclic aryl include, but are not limited to, dihydroindenyl,indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl. Thetricyclic aryl is anthracene or phenanthrene, or a bicyclic aryl fusedto a cycloalkyl, or a bicyclic aryl fused to a cycloalkenyl, or abicyclic aryl fused to a phenyl. Representative examples of tricyclicaryl ring include, but are not limited to, azulenyl, dihydroanthracenyl,fluorenyl, and tetrahydrophenanthrenyl.

The aryl groups of this invention can be substituted with 0, 1, 2, 3, 4or 5 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfinyl,alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio,alkylthioalkyl, alkynyl, arylalkyl, arylalkoxy, aryloxy, carboxy,carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen,haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, mercapto, nitro, —NZ¹Z²,and (NZ³Z⁴)carbonyl.

The term “arylalkoxy”, as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkoxy group,as defined herein. Representative examples of arylalkoxy include, butare not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, and5-phenylpentyloxy.

The term “arylalkyl”, as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and2-naphth-2-ylethyl.

The term “aryloxy”, as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of aryloxy include, but are not limited to,phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy,and 3,5-dimethoxyphenoxy.

The term “carbonyl”, as used herein, means a —C(O)— group.

The term “carboxy”, as used herein, means a —CO₂H group.

The term “carboxyalkyl”, as used herein, means a carboxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of carboxyalkylinclude, but are not limited to, carboxymethyl, 2-carboxyethyl, and3-carboxypropyl.

The terms “comprise”, “comprises” and “comprising”, as used herein, aretransitional terms, which are synonymous with “including,” “containing,”or “characterized by,” are inclusive or open-ended and do not excludeadditional, unrecited elements or method steps.

The term “concurrent administration” refers to administering the α4β2receptor ligand to a patient, who has been prescribed (or has consumed)at least one an α4β2 PAM, at an appropriate time so that the patient'ssymptoms may subside. This may mean simultaneous administration of anα4β2 PAM and an α4β2 receptor ligand, or administration of themedications at different, but appropriate times. Establishing such aproper dosing schedule will be readily apparent to one skilled in theart, such as a physician treating various pain states.

The term “cyano”, as used herein, means a —CN group.

The term “cyanoalkyl”, as used herein, means a cyano group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of cyanoalkyl include, butare not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.

The term “cycloalkenyl”, as used herein, means a cyclic hydrocarboncontaining from 3 to 8 carbons and containing at least one carbon-carbondouble bond formed by the removal of two hydrogens. Representativeexamples of cycloalkenyl include, but are not limited to,2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yl and3-cyclopenten-1-yl.

The term “cycloalkyl”, as used herein, means a monocyclic, bicyclic, ortricyclic ring system. Monocyclic ring systems are exemplified by asaturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms.Examples of monocyclic ring systems include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic ringsystems are exemplified by a bridged monocyclic ring system in which twoadjacent or non-adjacent carbon atoms of the monocyclic ring are linkedby an alkylene bridge of between one and three additional carbon atoms.Representative examples of bicyclic ring systems include, but are notlimited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, andbicyclo[4.2.1]nonane. Tricyclic ring systems are exemplified by abicyclic ring system in which two non-adjacent carbon atoms of thebicyclic ring are linked by a bond or an alkylene bridge of between oneand three carbon atoms. Representative examples of tricyclic-ringsystems include, but are not limited to, tricyclo[3.3.1.0^(3,7)]nonaneand tricyclo[3.3.1.1^(3,7)]decane (adamantane).

The cycloalkyl groups of the invention are optionally substituted with1, 2, 3, 4 or 5 substituents selected from the group consisting ofalkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl,alkylthio, alkylthioalkyl, alkynyl, carboxy, cyano, formyl, haloalkoxy,haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, oxo, —NZ¹Z², and(NZ³Z⁴)carbonyl.

The term “cycloalkylalkyl”, as used herein, means a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of cycloalkylalkylinclude, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl,cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.

The term “dialkylamino,” as used herein, refers to two independent alkylgroups, as defined herein, appended to the parent molecular moietythrough an amino group, as defined herein. Representative examples ofdialkylamino include, but are not limited to, dimethylamino,diethylamino, ethylmethylamino, butylmethylamino, ethylhexylamino, andthe like.

The term “dialkylaminoalkyl”, as used herein, means a dialkyl group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of dialkylaminoalkylinclude, but are not limited to, dimethylaminomethyl anddimethylaminoethyl.

The term “dialkylsulfonylformimidamide” as used herein, means a—SO₂N═CH—N(alkyl)₂ group.

The term “formyl”, as used herein, means a —C(O)H group.

The term “formylalkyl”, as used herein, means a formyl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of formylalkyl include, butare not limited to, formylmethyl and 2-formylethyl.

The term “halo” or “halogen”, as used herein, means —Cl, —Br, —I or —F.

The term “haloalkoxy”, as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, and pentafluoroethoxy.

The term “haloalkyl”, as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “haloalkylcarbonyl”, as used herein, means a haloalkyl group,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofhaloalkylcarbonyl include, but are not limited to,trichloromethylcarbonyl and trifluoromethylcarbonyl.

The term “heteroaryl”, as used herein, means a monocyclic heteroaryl ora bicyclic heteroaryl. The monocyclic heteroaryl is a 5 or 6 memberedring that contains at least one heteroatom selected from the groupconsisting of nitrogen, oxygen and sulfur. The 5 membered ring containstwo double bonds and the 6 membered ring contains three double bonds.The 5 or 6 membered heteroaryl is connected to the parent molecularmoiety through any carbon atom or any substitutable nitrogen atomcontained within the heteroaryl, provided that proper valance ismaintained. Representative examples of monocyclic heteroaryl include,but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, and triazinyl. The bicyclic heteroaryl consists of amonocyclic heteroaryl fused to a phenyl, or a monocyclic heteroarylfused to a cycloalkyl, or a monocyclic heteroaryl fused to acycloalkenyl, or a monocyclic heteroaryl fused to a monocyclicheteroaryl, or a monocyclic heteroaryl fused to a monocyclicheterocycle. The bicyclic heteroaryl is connected to the parentmolecular moiety through any carbon atom or any substitutable nitrogenatom contained within the bicyclic heteroaryl, provided that propervalance is maintained. Representative examples of bicyclic heteroarylinclude, but are not limited to, azaindolyl, benzimidazolyl,benzo[d][1,3]dioxolyl, benzofuranyl, benzoxadiazolyl,benzo[d]imidazolyl, benzo[d]imidazle-2(3H)-thione, benzoisoxazole,benzoisothiazole, benzooxazole, benzooxazolone,benzo[d][1,2,3]thiadiazolyl, 1,3-benzothiazolyl, benzothiophenyl,benzo[d][1,2,3]triazolyl, cinnolinyl, 2,2-difluorobenzo[d][1,3]dioxolyl,furopyridine, imidazopyridinyl, indolyl, indazolyl, isobenzofuran,isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine,pyrazolopyrimidinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl,thienopyridinyl, and [1,2,4]triazolopyridinyl.

The heteroaryl groups of the invention are optionally substituted with1, 2, 3 or 4 substituents independently selected from the groupconsisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio,alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl,formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto,nitro, —NZ¹Z², (NZ³Z⁴)carbonyl and oxo. Heteroaryl groups of theinvention that are substituted with a hydroxyl group may be present astautomers. The heteroaryl groups of the invention encompass alltautomers including non-aromatic tautomers.

The term “heterocycle” or “heterocyclic”, as used herein, means amonocyclic heterocycle, a bicyclic heterocycle or a tricyclicheterocycle. The monocyclic heterocycle is a 3, 4, 5, 6 or 7 memberedring containing at least one heteroatom independently selected from thegroup consisting of O, N, and S. The 3 or 4 membered ring contains 1heteroatom selected from the group consisting of O, N and S. The 5membered ring contains zero or one double bond and one, two or threeheteroatoms selected from the group consisting of O, N and S. The 6 or 7membered ring contains zero, one or two double bonds and one, two orthree heteroatoms selected from the group consisting of O, N and S. Themonocyclic heterocycle is connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within themonocyclic heterocycle. Representative examples of monocyclicheterocycle include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl,thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, andtrithianyl. The bicyclic heterocycle is a 5 or 6 membered monocyclicheterocycle fused to a phenyl group, or a 5 or 6 membered monocyclicheterocycle fused to a cycloalkyl, or a 5 or 6 membered monocyclicheterocycle fused to a cycloalkenyl, or a 5 or 6 membered monocyclicheterocycle fused to a monocyclic heterocycle. The bicyclic heterocycleis connected to the parent molecular moiety through any carbon atom orany nitrogen atom contained within the bicyclic heterocycle.Representative examples of bicyclic heterocycle include, but are notlimited to, 1,3-benzodioxolyl, 1,3-benzodithiolyl,2,3-dihydro-1,4-benzodioxinyl, benzodioxolyl,2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl, chromenyl and1,2,3,4-tetrahydroquinolinyl. The tricyclic heterocycle is a bicyclicheterocycle fused to a phenyl, or a bicyclic heterocycle fused to acycloalkyl, or a bicyclic heterocycle fused to a cycloalkenyl, or abicyclic heterocycle fused to a monocyclic heterocycle. The tricyclicheterocycle is connected to the parent molecular moiety through anycarbon atom or any nitrogen atom contained within the tricyclicheterocycle. Representative examples of tricyclic heterocycle include,but are not limited to, 2,3,4,4a,9,9a-hexahydro-1H-carbazolyl,5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furanyl, and5a,6,7,8,9,9a-hexahydrodibenzo[b,d]thienyl.

The heterocycles of this invention are optionally substituted with 1, 2,3 or 4 substituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl,alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl,alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy,haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, mercapto, oxo, —NZ¹Z²and (NZ³Z⁴)carbonyl.

The term “hydroxy”, as used herein, means an —OH group.

The term “hydroxyalkyl”, as used herein, means at least one hydroxygroup, as defined herein, is appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “hydroxy-protecting group” or “O-protecting group” means asubstituent which protects hydroxyl groups against undesirable reactionsduring synthetic procedures. Examples of hydroxy-protecting groupsinclude, but are not limited to, substituted methyl ethers, for example,methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,2-(trimethylsilyl)-ethoxymethyl, benzyl, and triphenylmethyl;tetrahydropyranyl ethers; substituted ethyl ethers, for example,2,2,2-trichloroethyl and t-butyl; silyl ethers, for example,trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclicacetals and ketals, for example, methylene acetal, acetonide andbenzylidene acetal; cyclic ortho esters, for example, methoxymethylene;cyclic carbonates; and cyclic boronates. Commonly usedhydroxy-protecting groups are disclosed in T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley &Sons, New York (1999).

The term “lower alkenyl”, as used herein, is a subset of alkenyl, asdefined herein, and means an alkenyl group containing from 2 to 4 carbonatoms. Examples of lower alkenyl are ethenyl, propenyl, and butenyl.

The term “lower alkoxy”, as used herein, is a subset of alkoxy, asdefined herein, and means a lower alkyl group, as defined herein,appended to the parent molecular moiety through an oxygen atom, asdefined herein. Representative examples of lower alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, andtert-butoxy.

The term “lower alkyl”, as used herein, is a subset of alkyl, as definedherein, and means a straight or branched chain hydrocarbon groupcontaining from 1 to 4 carbon atoms. Examples of lower alkyl are methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andtert-butyl.

The term “lower haloalkoxy”, as used herein, is a subset of haloalkoxy,as defined herein, and means a straight or branched chain haloalkoxygroup containing from 1 to 4 carbon atoms. Representative examples oflower haloalkoxy include, but are not limited to, trifluoromethoxy,trichloromethoxy, dichloromethoxy, fluoromethoxy, and pentafluoroethoxy.

The term “lower haloalkyl”, as used herein, is a subset of haloalkyl, asdefined herein, and means a straight or branched chain haloalkyl groupcontaining from 1 to 4 carbon atoms. Representative examples of lowerhaloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, dichloromethyl, fluoromethyl, and pentafluoroethyl.

The term “mammal” includes humans and animals, such as cats, dogs,swine, cattle, horses, and the like.

The term “methylenedioxy”, as used herein, means a —OCH₂O— group whereinthe oxygen atoms of the methylenedioxy are attached to the parentmolecular moiety through two adjacent carbon atoms.

The term “nitrogen protecting group”, as used herein, means those groupsintended to protect an amino group against undesirable reactions duringsynthetic procedures. Preferred nitrogen protecting groups are acetyl,benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl,tert-butoxycarbonyl (Boc), tert-butylacetyl, trifluoroacetyl, andtriphenylmethyl (trityl).

The term “mercapto”, as used herein, means a —SH group.

The term “nitro”, as used herein, means a —NO₂ group.

The term “NZ¹Z²”, as used herein, means two groups, Z¹ and Z², which areappended to the parent molecular moiety through a nitrogen atom. Z¹ andZ² are each independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, arylalkyl, andformyl. In certain instances within the invention, Z¹ and Z² takentogether with the nitrogen atom to which they are attached form aheterocyclic ring. Representative examples of NZ₁Z₂ include, but are notlimited to, amino, methylamino, acetylamino, acetylmethylamino,phenylamino, benzylamino, azetidinyl, pyrrolidinyl and piperidinyl.

The term “NZ³Z⁴”, as used herein, means two groups, Z³ and Z⁴, which areappended to the parent molecular moiety through a nitrogen atom. Z³ andZ⁴ are each

The term “oxo”, as used herein, means a ═O moiety.

The term “pharmaceutically acceptable amide,” as used herein, refers tothose amides, which retain, upon hydrolysis of the amide bond, thebiological effectiveness and properties of the carboxylic acid and arenot biologically or otherwise undesirable. Pharmaceutically acceptableamides of the invention can be derived from ammonia, primary C₁₋₆ alkylamines and secondary C₁₋₆ dialkyl amines. In the case of secondaryamines, the amine can also be in the form of a 5- or 6-memberedheterocycle containing one nitrogen atom. Amides derived from ammonia,C₁₋₃ alkyl primary amides and C₁₋₂ dialkyl secondary amides arepreferred. Amides of the compounds of formulas (I) and (II) can beprepared according to conventional methods. Pharmaceutically acceptableamides can be prepared from compounds containing primary or secondaryamine groups by reaction of the compound that contains the amino groupwith an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide.In the case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine,for example with methylamine, diethylamine, piperidine. They also can beprepared by reaction of the compound with an acid such as sulfuric acidand an alkylcarboxylic acid such as acetic acid, or with acid and anarylcarboxylic acid such as benzoic acid under dehydrating conditions aswith molecular sieves added. The composition can contain a compound ofthe invention in the form of a pharmaceutically acceptable prodrug.

The term “pharmaceutically acceptable prodrug” or “prodrug” as usedherein, represents those prodrugs of the compounds of the inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use.Prodrugs of the invention can be rapidly transformed in vivo to a parentcompound of the invention, for example, by hydrolysis in blood. Athorough discussion is provided in Higuchi T., et al., Pro-drugs asNovel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and inEdward B. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press (1987).

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, solid, semi-solid or liquid filler, diluent, encapsulatingmaterial, or formulation auxiliary of any type. Examples oftherapeutically suitable excipients include sugars; cellulose andderivatives thereof, oils; glycols; solutions; buffering, coloring,releasing, coating, sweetening, flavoring, and perfuming agents; and thelike. These therapeutic compositions can be administered parenterally,intracisternally, orally, rectally, intraveneously, orintraperitoneally.

The term “sulfinyl”, as used herein, means a —S(O)— group.”

The term “sulfonamide”, as used herein means an amino, alkylamino, ordialkylamino group, as defined herein, appended to the parent molecularmoiety through a sulfonyl group, as defined herein. Representativeexamples include, but are not limited to, aminosulfonyl,methylaminosulfonyl, and diethylaminosulfonyl.

The term “sulfonyl”, as used herein, means a —SO₂— group.

The term “tautomer”, as used herein, means a proton shift from one atomof a compound to another atom of the same compound wherein two or morestructurally distinct compounds are in equilibrium with each other.

The term “radiolabel” refers to a compound in which at least one of theatoms is a radioactive atom or radioactive isotope, wherein theradioactive atom or isotope spontaneously emits gamma rays or energeticparticles, for example alpha particles or beta particles, or positrons.Examples of such radioactive atoms include, but are not limited to, ³H(tritium), ¹⁴C, ¹¹C, ¹⁵O, ¹⁸F, ³⁵S, ¹²³I, and ¹²⁵I. Compounds suitablefor the composition, method, and article of manufacture for theinvention are any chemical compounds for which α4β2 nicotinic receptoractivity can be identified.

The term “treatment” or “treating” includes any process, action,application, therapy, or the like, wherein a subject, including human,is provided medical aid with the object of improving the subject'scondition, directly or indirectly, or slowing the progression of acondition or disorder in the subject.

Although typically it may be recognized that an asterisk is used toindicate that the exact subunit composition of a receptor is uncertain,for example α4β2* indicates a receptor that contains the α4 and β2subunit proteins in combination with other subunits.

It has been found that the efficacy of nicotinic receptor ligandssurprisingly can be improved by combining a nicotinic acetylcholinereceptor ligand, particularly an α4β2 receptor ligand (agonist, partialagonist), with a nicotinic acetylcholine receptor α4β2 subtype selectivepositive allosteric modulator (PAM). Such combinations are highlyefficient for improving the efficacy of α4β2 ligand for treatment ofpain and other disease indications such as cognitive deficits whencompared to administration of an α4β2 receptor ligand alone.

Nicotinic Acetylcholine Subtype α4β2 Receptor Ligands

Nicotinic acetylcholine subtype α4β2 receptor ligands modulate thefunction by altering the activity of the receptor. Suitable compoundsalso can be partial agonists that partially block or partially activatethe α4β2 receptor or agonists that activate the receptor. Nicotinicacetylcholine receptor α4β2 receptor ligands suitable for the inventioncan include full agonists or partial agonists. Compounds modulatingactivity of nicotinic acetylcholine receptor α4β2 subtype are suitablefor the invention regardless of the manner in which they interact withthe receptor.

One manner for characterizing α4β2 receptor ligands is by a bindingassay. [³H]-Cytisine binding values (“K_(i) Cyt”) of compounds of theinvention ranged from about 0.001 nanomolar to greater than 100micromolar. Preferred compounds for the composition demonstrate bindingvalues of from about 0.001 nanomolar to 10 micromolar. The [³H]-cytisinebinding assays have been well reported; however, further details forcarrying out the assays can be obtained in International Publication No.WO 99/32480; U.S. Pat. Nos. 5,948,793 and 5,914,328; WO 2004/018607;U.S. Pat. No. 6,809,105; WO 00/71534; and U.S. Pat. No. 6,833,370.

Accordingly, α4β2 receptor ligands suitable for the invention can becompounds of various chemical classes. Particularly, some examples ofα4β2 receptor ligands suitable for the invention include, but are notlimited to heterocyclic ether derivatives (see, for example,International Publication No. WO 99/32480, published Jul. 1, 1999; U.S.Pat. No. 5,948,793, issued Sep. 7, 1999, and U.S. Pat. No. 5,914,328,issued Jun. 22, 1999); N-substituted diazabicyclic derivatives (see forexample International Publication No. WO 2004/0186107, published Sep.23, 2004, and U.S. Pat. No. 6,809,105, issued Oct. 26, 2004);heterocyclic substituted amino azacycles (see for example, InternationalPublication No. WO 00/71534, published Nov. 30, 2000, and U.S. Pat. No.6,833,370, issued Dec. 21, 2004); all of which are hereby incorporatedby reference in their entirety. Further description and methods forpreparing the compounds have been reported in the patents, patentpublications, and international patent publications cited.

Additional examples of α4β2 receptor ligands suitable for the inventioninclude, but are not limited to aryl-fused azapolycyclic compounds (seefor example, International Publication No. WO 2001062736, published Aug.30, 2001); aryl-substituted olefinic amine compounds (see for example,International Publication Nos. WO 9965876, published Dec. 23, 1999, andWO 00/75110, published Dec. 14, 2000); pyridopyranoazepine derivatives(see for example, U.S. Pat. No. 6,538,003, published Mar. 25, 2003);benzylidene- and cinnamylidene-anabaseines (see for examples,International Publication No. WO 99/10338, published Mar. 4, 1999); and3-pyridoxylalkyl heterocyclic ether compounds (see for example,International Publication No. WO 96/040682, published Dec. 19, 1996);all of which are hereby incorporated by reference in their entirety.Further description and methods for preparing the compounds have beenreported in the patents and international patent publications cited.

Other compounds reported as demonstrating α4β2 ligands include, but arenot limited to, TC-1734 (ispronicline), GTS-21, 4-hydroxy-GTS-21,TC-5619, TC-2696, dianicline and varenicline, which are all described inthe publicly available literature.

Specific examples of compounds contemplated for the α4β2 receptorligands include, but are not limited to,

-   5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine;-   (3R)-1-pyridin-3-ylpyrrolidin-3-amine;-   2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine;-   3-(5,6-dichloro-pyridin-3-yl)-1S,5S-3,6-diazabicyclo[3.2.0]heptane;-   (R,R)-1-(pyridin-3-yl)octahydro-pyrrolo[3,4-b]pyrrole;-   6,10-methano-6H-pyrazino[2,3-h][3]benzazepine;-   7,8,9,10-tetrahydro-(2S,4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine;-   (2S,4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine;-   (2S,4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine;-   (2S,4E)-N-methyl-3-pyrimidine-4-penten-2-amine;-   (5aS,8S,10aR)-5a,6,9,10-tetrahydro-7H,11H-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepine;-   3-[1-(2,4-dimethoxy-phenyl)-meth-(E)-ylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;    and-   3-[1-(2-methoxy-4-hydroxyphenyl)-meth-(E)-ylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;

or pharmaceutically acceptable salts thereof.

Nicotinic Acetylcholine Subtype α4β2 Receptor Positive AllostericModulators

Positive allosteric modulators (PAMs) are compounds that potentiatereceptor responses to acetylcholine without themselves triggeringreceptor activation or desensitization, or either, of the receptor.

One manner for characterizing α4β2 positive allosteric modulatoractivity is by characterization in human HEK cells expressing the humannicotinic acetylcholine receptor subtype α4β2, particularly by use ofFluorescent Image Plate Reader technology. Such assay has been reportedand further details for carrying out the assays can be obtained inInternational Publication Nos. WO 2006/114400, published Nov. 2, 2006.Another method to identify and characterize allosteric modulatoractivity is by expressing the α4β2 subunits in Xenopus oocytes or celllines, and by measuring effects on ligand-evoked current responses aspreviously described (Curtis L, et al., Molecular Pharmacology, 61:127-135, 2002).

Steroid hormones represent a family of molecules with varying modulatoryeffects on nAChRs as well as other members of the LGIC superfamily. Forexample, positive allosteric modulation of human α4β2 nAChRs expressedeither in Xenopus oocytes or in human embryonic kidney cells wasreported with 17β-estradiol (Curtis L, et al., Molecular Pharmacology,61: 127-135, 2002). Examples of compounds reported as selective α4β2positive allosteric modulators are oxadiazole derivatives, for exampleas described in WO 2006/114400.

Another suitable α4β2 positive allosteric modulator is3,5-diphenylisoxazole, which is commercially available from SigmaAldrich, St. Louis, Mo., USA.

Other suitable examples of α4β2 positive allosteric modulators include,but are not limited to, oxadiazole derivatives. Suitable oxadiazolederivatives can include 1,2,4-oxadiazole derivatives and1,3,4-oxadiazole derivatives. Examples of 1,3,4-oxadiazole derivativesare described in co-pending U.S. Patent Application No. 61/000,295,filed on Apr. 12, 2007, wherein the methods of preparation disclosed areincorporated by reference herein. Such compounds have the formula (I):

or are pharmaceutically acceptable salts and prodrugs thereof, wherein

X is a bond, O, NR¹, S, or C₁-C₃ alkylene;

Y represents a monocyclic aryl, cycloalkyl, heterocycle, or heteroarylgroup;

Ar¹ represents a monocyclic aryl or a heteroaryl group; and

R¹ is hydrogen, alkyl, haloalkyl or arylalkyl.

X is selected from a bond, O, NR¹, S, or C₁-C₃ alkylene, wherein R¹ isselected from hydrogen, alkyl, haloalkyl, and arylalkyl. Preferably, Xis a bond. Preferably, R¹ is hydrogen or alkyl.

Y represents a monocyclic aryl, cycloalkyl, heterocycle, or heteroarylgroup, which can be substituted or unsubstituted with substituents.Examples of suitable heterocycle groups can include, but are not limitedto, pyrrolidine, piperidine, and the like. Examples of suitableheteroaryl groups can include, but are not limited to, thienyl, furanyl,pyridinyl, pyrazinyl, and the like. A preferred monocyclic aryl group issubstituted or unsubstituted phenyl. Suitable substituents for themonocyclic aryl, heterocycle, or heteroaryl group are, for example,alkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, hydroxyl, alkoxy,haloalkoxy, nitro, and cyano.

Ar₁ represents a monocyclic aryl, such as substituted or unsubstitutedphenyl, or heteroaryl group. Examples of suitable heteroaryl groupsinclude, but are not limited, thienyl, furanyl, pyrrolyl, pyrazolyl,thiazolyl, 1,3,4-thiadiazolyl, and pyridinyl, each of which can beunsubstituted or substituted with one, two, or three substituentsselected from alkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl,hydroxyl, alkoxy, haloalkoxy, nitro, cyano, and amino.

In one embodiment, suitable 2,5-disubstituted-1,3,4-oxadiazolederivatives can have the formula (I) wherein X is a bond; Y is aryl,cycloalkyl, heterocycle, or heteroaryl; and Ar¹ is monocyclic aryl orheteroaryl.

In another embodiment, suitable 2,5-disubstituted-1,3,4-oxadiazolederivatives can have the formula (I) wherein X is a bond; Y ismonocyclic cycloalkyl, phenyl, thienyl, furyl, pyridinyl, pyrazinyl,pyrrolidinyl, or piperidinyl optionally substituted with one or more ofthe substituents selected from the group consisting of alkyl, halogen,haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano; and Ar¹ isphenyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl,1,3,4-thiadiazolyl, pyrimidinyl, pyrazinyl, or pyridinyl optionallysubstituted with one or more of the substituents selected from the groupconsisting of alkyl, alkylcarbonyl, alkylsulfonyl, alkylthio, arylalkyl,aryloxy, arylalkyloxy, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy,nitro, cyano, and NZ¹Z², wherein Z¹ and Z² are hydrogen, alkyl,alkylcarbonyl, alkoxycarbonyl, aryl, arylalkyl, or formyl.

In another embodiment, the suitable 2,5-disubstituted-1,3,4-oxadiazolederivatives can have the formula (I) wherein X is a bond; Y is pyridyl;and Ar¹ is phenyl, pyrimidinyl, pyrazinyl, or pyridinyl optionallysubstituted with one or more of the substituents selected from the groupconsisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy,nitro, cyano, and NZ¹Z², wherein Z¹ and Z² are hydrogen, alkyl,alkylcarbonyl, alkoxycarbonyl, aryl, arylalkyl, or formyl.

Other suitable examples of compounds reported as α4β2 positiveallosteric modulators are oxadiazole derivatives, for example asdescribed in WO 2006/114400, published Nov. 2, 2006. Further examples ofoxadiazole compounds that are suitable as α4β2 positive allostericmodulators are also provided in WO 02/100826, published Dec. 19, 2002.

Yet other suitable examples of α4β2 positive allosteric modulatorsinclude, but are not limited to, compounds of the formula (II):

or are pharmaceutically acceptable salts thereof, wherein

Ar² is aryl or heteroaryl, wherein the aryl or heteroaryl is substitutedor unsubstituted, and, when substituted, the aryl or heteroaryl issubstituted with 0, 1, 2, 3, or 4 substituents selected from halo, C₁-C₆haloalkyl, C₆-C₁₀ aryl, C₄-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₅-C₁₀ heteroaryl, C₄-C₁₀ heterocycle, C₁-C₆ alkyl, —(C₁-C₆alkyl)NHC(O)O—(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆ alkylcarbonyl,amino, hydroxyl, haloalkyl-C(O)—, haloalkyl-SO₂—, alkyl-SO₂—, —SO₂NH₂,—SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, cyano, nitro, C₁-C₆ acylamino,C₁-C₆ alkoxy, —C(O)NH₂, —C(O)O—(C₁-C₆ alkyl), and carboxy; and

Ar³ is aryl or heteroaryl, wherein the aryl or heteroaryl is optionallysubstituted, and, when substituted, the aryl or heteroaryl issubstituted with a substituent selected from halo, C₁-C₆ haloalkyl,C₆-C₁₀ aryl, C₄-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₅-C₁₀heteroaryl, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, amino, hydroxyl,haloalkyl-SO₂—, cyano, nitro, C₁-C₆ acylamino, C₁-C₆ alkoxy, —N(C₁-C₆alkyl)₂, and carboxy.

In one embodiment, suitable 3,5-disubstituted-1,2,4-oxadiazolederivatives can have the formula (I) wherein Ar² is substitutedmonocyclic aryl or monocyclic heteroaryl, which can be substituted orunsubstituted, and Ar³ is substituted monocyclic aryl or heteroaryl,which can be substituted or unsubstituted. When the aryl or heteroarylgroup for Ar² is substituted the substituent is selected from halo,C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₄-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₅-C₁₀ heteroaryl, C₄-C₁₀ heterocycle, C₁-C₆ alkyl, —(C₁-C₆alkyl)NHC(O)O—(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆ alkylcarbonyl,amino, hydroxyl, haloalkyl-C(O)—, haloalkyl-SO₂—, alkyl-SO₂—, —SO₂NH₂,—SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, cyano, nitro, C₁-C₆ acylamino,C₁-C₆ alkoxy, —C(O)NH₂, —C(O)O—(C₁-C₆ alkyl), and carboxy. When the arylor heteroaryl group for Ar³ is substituted the substituent is selectedfrom halo, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₄-C₇ cycloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₅-C₁₀ heteroaryl, C₁-C₆ alkyl, C₁-C₆hydroxyalkyl, amino, hydroxyl, haloalkyl-SO₂—, cyano, nitro, C₁-C₆acylamino, C₁-C₆ alkoxy, —N(C₁-C₆ alkyl)₂, and carboxy. Preferred formonocyclic heteroaryl are pyridine-3-yl, pyridine-4-yl, andpyridine-2(1H)-one.

In another embodiment, suitable 3,5-disubstituted-1,2,4-oxadiazolederivatives can have the formula (II) wherein Ar² is pyridinyl, whichcan be substituted or unsubstituted, or substituted phenyl; and Ar³ ispyridinyl, which can be substituted or unsubstituted, or substitutedphenyl. The pyridinyl group, when substituted, is substituted withfluoro. The phenyl group is substituted with cyano or halo. It ispreferred that the pyridinyl group for Ar² or Ar³ is pyridin-3-yl. Thepreferred phenyl group is substitute with fluoro, sulfonamide or cyano,and preferably cyano.

Specific examples of α4β2 positive allosteric modulators are, forexample, 3,5-disubstituted-1,2,4-oxadiazole derivatives, such as:

-   3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile;-   3,5-di(pyridin-3-yl)-1,2,4-oxadiazole;-   3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile;-   3-(5-(6-fluoropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile;-   5-(5-bromopyridin-3-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   3-(pyridin-3-yl)-5-(3-(trifluoromethylsulfonyl)phenyl)-1,2,4-oxadiazole;-   3-(3-(6-methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile;-   5-(5-(pyrrol-1-yl)pyridin-3-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)pyridin-3-ol;-   5-(3,4-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(2,3-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(pyrazin-2-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(3,5-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(2,3,5-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(2,4,5-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(2,5-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(4-chloro-2,5-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(5-methylpyrazin-2-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   4-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile;-   2,3,6-trifluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol;-   2-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol;-   2-fluoro-4-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol;-   5-(3-chloro-4-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(3,4-dichlorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   2-nitro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol;-   5-(2,3,6-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   2,2,2-trifluoro-1-(4-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)ethanone;-   5-(3-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(4-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(2-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   3-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile;-   3-(2,3-difluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;-   3-(3,4-difluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(2,6-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzenesulfonamide;-   5-(2,4-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(2,3,4-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(3,4,5-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(4-chloro-3-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(3-nitrophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(3-(methylsulfonyl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   3-(2-chloropyridin-4-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;-   3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzamide;-   4-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)pyridin-2(1H)-one;-   tert-butyl 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzoate;-   2-amino-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol;-   N,N-dimethyl-4-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;-   3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzoic acid;-   5-(3-(1H-tetrazol-5-yl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   N,N-diethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzenesulfonamide;-   2-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile;-   3-(3-(1H-tetrazol-5-yl)phenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;-   3-(6-chloropyridin-3-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(6-chloropyridin-3-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   5-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)pyridin-2(1H)-one;-   5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)pyridin-2(1H)-one;-   N-methyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzenesulfonamide;-   3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)aniline;-   (3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)methanamine;-   5-(2-chloropyridin-4-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   4-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)pyridin-2(1H)-one;-   tert-butyl 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzylcarbamate;-   5-(3-bromophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)pyrrolidin-2-one;-   tert-butyl 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenylcarbamate;-   N,N-dimethyl-1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)methanamine;-   5-(3-(piperazin-1-yl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)ethanone;-   3-(6-chloropyridin-3-yl)-5-(2,3-difluorophenyl)-1,2,4-oxadiazole;-   3-(6-chloropyridin-3-yl)-5-(3,4-difluorophenyl)-1,2,4-oxadiazole;-   (R)-3-(pyridin-3-yl)-5-(3-(pyrrolidin-2-yl)phenyl)-1,2,4-oxadiazole;-   5-(3-(1H-pyrazol-3-yl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;-   1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)ethanol;-   3-(3-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile;-   3-(4-fluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;-   3-(5-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile;-   3-(5-(2-fluoropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile, and-   3-fluoro-5-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile;

or pharmaceutically acceptable salts thereof.

Other specific examples of α4β2 positive allosteric modulators are, forexample, 2,5-disubstituted-1,3,4-oxadiazole derivatives, such as:

-   2-(imidazo[1,5-a]pyridin-6-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole-   2,5-di(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(5-bromopyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(pyridin-3-yl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazole;-   2-(pyridin-3-yl)-5-o-tolyl-1,3,4-oxadiazole;-   2-(pyridin-3-yl)-5-m-tolyl-1,3,4-oxadiazole;-   2-(pyridin-3-yl)-5-p-tolyl-1,3,4-oxadiazole;-   2-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol;-   3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol;-   4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol;-   2-(3-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(4-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2-fluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(3-fluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(4-fluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2-chlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(3-chlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(4-chlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2-bromophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(3-bromophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(4-bromophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)benzonitrile;-   4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)benzonitrile;-   N,N-dimethyl-3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)aniline;-   N,N-dimethyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)aniline;-   2-(pyridin-3-yl)-5-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole;-   2-(pyridin-3-yl)-5-(3-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole;-   2-(4-phenoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(4-(benzyloxy)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(3,4-dimethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(3,5-dimethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2,5-dimethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2,4-dimethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(3,4-dimethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2,3-dimethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2,4-dimethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2,5-dimethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2,4-dimethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(3,5-dimethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(benzo[d][1,3]dioxol-5-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(pyridin-3-yl)-5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazole;-   2-(3,4-dichlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2,4-dichlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2,5-dichlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(3,4-dichlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   5-methyl-2-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol;-   2-methyl-5-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol;-   2-(3-fluoro-2-methylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(5-fluoro-2-methylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(3-fluoro-4-methylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2,3-difluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2,4-difluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2,5-difluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(3,5-difluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   1-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)ethanone;-   2-(4-isopropylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(3-methoxy-4-methylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(4-ethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(4-(methylthio)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(3-fluoro-4-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(naphthalen-1-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(naphthalen-2-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   4-chloro-2-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol;-   2-(4-tert-butylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   N-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)acetamide;-   2-(4-propoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(4-isopropoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(5-chloro-2-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(4-fluoronaphthalen-1-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   N,N-diethyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)aniline;-   2-(4-butoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2-methoxy-4-(methylthio)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(4-(methylsulfonyl)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2-chloro-5-(methylthio)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2-fluoro-5-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2-chloro-5-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2-phenethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2-bromo-5-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(5-bromo-2-chlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2-iodophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(3-iodophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(4-iodophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(pyridin-3-yl)-5-(pyrimidin-5-yl)-1,3,4-oxadiazole;-   2-(5-methylpyrazin-2-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2-chloro-6-methylpyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2-(ethylthio)pyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2,6-dimethoxypyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2-(methylthio)pyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   5-chloro-3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-ol;-   2-(2,6-dichloro-5-fluoropyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2,5-dichloropyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(6-chloropyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2,6-dichloropyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(2-chloropyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;-   2-(pyridin-3-yl)-5-(quinolin-3-yl)-1,3,4-oxadiazole; and-   2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

or pharmaceutically acceptable salts thereof.

Novel α4β2 PAMs of the Present Invention

Various embodiments of the invention described herein include, but arenot limited to, pharmaceutically acceptable salts, amides, esters andprodrugs thereof.

Another embodiment of the invention is a compound of formula (II),wherein Ar² and Ar³ are independently aryl, pyrazinyl, pyridazinyl,pyrimidinyl, triazinyl, or a bicyclic heteroaryl, substitutedindependently with 0, 1, 2, 3, or 4 substitutents selected from thegroup consisting of alkoxy, alkoxycarbonyl, alkoxycarbonylamino,alkoxycarbonylaminoalkyl, alkyl, alkylamino, alkylcarbonyl,alkylsulfonyl, amido, amino, aminoalkyl, carboxy, dialkylamino,dialkylaminoalkyl, halo, haloalkyl, haloalkylcarbonyl, heteroaryl,heterocycle, hydroxy, hydroxyalkyl, cyano, nitro, oxo, sulfonamide anddialkylsulfonylformimidamide; provided that when one of Ar² and Ar³ ispyridinyl or aryl, the other is not pyridinyl; when Ar³ is pyridinyl,Ar² is not pyrazinyl.

Another embodiment of the invention is a compound of formula (II),wherein Ar² is optionally substituted phenyl.

Another embodiment of the invention is a compound of formula (II),wherein Ar² is optionally substituted pyridinyl or pyrimidinyl.

Another embodiment of the invention is a compound of formula (II),wherein Ar² is optionally substituted bicyclic heteroaryl.

Another embodiment of the invention is a compound of formula (II),wherein Ar³ is optionally substituted pyridinyl, pyrimidinyl orpyridazinyl.

Another embodiment of the invention is a compound of formula (II),wherein Ar³ is optionally substituted bicyclic heteroaryl.

Another embodiment of the invention is a compound of formula (II),wherein Ar² and Ar³ are independently, optionally substituted monocyclicor bicyclic heteroaryl, wherein the monocyclic heteroaryl issix-membered heterocycle, provided that when one of Ar² and Ar³ ispyridinyl, the other is not pyridinyl, and when Ar³ is pyridinyl, Ar² isnot pyrazinyl.

Another embodiment of the invention is a compound of formula (II),wherein Ar² and Ar³ are independently, optionally substituted pyrazinyl,pyridazinyl, pyridinyl, pyrimidinyl, triazinyl, or a bicyclicheteroaryl.

Another embodiment of the invention is a compound of formula (II),wherein Ar² and Ar³ are independently, optionally substituted phenyl,pyridazinyl, pyridinyl, pyrimidinyl, or bicyclic heteroaryl.

Another embodiment of the invention is a compound of formula (II),wherein one of Ar² and Ar³ is optionally substituted bicyclicheteroaryl.

Another embodiment of the invention is a compound of formula (II),wherein one of Ar² and Ar³ is optionally substituted bicyclic heteroarylselected from the group consisting of benzimidazolyl,benzo[d][1,3]dioxolyl, benzofuranyl, benzo[d]imidazolyl, benzooxazole,benzo[d][1,2,3]thiadiazolyl, 1,3-benzothiazolyl,benzo[d][1,2,3]triazolyl, 2,2-difluorobenzo[d][1,3]dioxolyl,imidazopyridinyl, indolyl, indazolyl, pyrazolopyrimidinyl,pyrrolopyridinyl, and [1,2,4]triazolopyridinyl.

Another embodiment of the invention is a compound of formula (II),selected from the group of compounds exemplified in Examples 79-134described below.

Another embodiment of the invention is a compound of formula (II),selected from the group of compounds exemplified in Examples 79-105described below.

Another embodiment of the invention is a compound of formula (II),selected from the group of compounds exemplified in Examples 79-82,85-89, 101, and 103-105 described below.

Another embodiment of the invention is a compound of formula (II),selected from the group of compounds exemplified in Examples 90 and 102described below.

Another embodiment of the invention is a compound of formula (II),selected from the group of compounds exemplified in Examples 83-84 and92-100 described below.

Another embodiment of the invention is a compound of formula (II),selected from the group of compounds exemplified in Examples 90-91described below.

Another embodiment of the invention is a compound of formula (II),selected from the group of compounds exemplified in Examples 106-134described below.

Another embodiment of the invention is a compound of formula (II),selected from the group of compounds exemplified in Examples 106-118,123-131 and 134 described below.

Another embodiment of the invention is a compound of formula (II),selected from the group of compounds exemplified in Examples 119-122 and132-133 described below.

Another embodiment of the invention is5-(2,3-difluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(pyridin-3-yl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is2-fluoro-N,N-dimethyl-4-(3-(pyrimidin-5-yl)-1,2,4-oxadiazol-5-yl)aniline.

Another embodiment of the invention is3-(3-(pyrimidin-5-yl)-1,2,4-oxadiazol-5-yl)benzonitrile.

Another embodiment of the invention is5-(3,4-difluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(pyridazin-4-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention isN,N-dimethyl-N′-(4-(3-(pyrimidin-5-yl)-1,2,4-oxadiazol-5-yl)phenylsulfonyl)-formimidamide.

Another embodiment of the invention is5-(4-fluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(3-fluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(pyrimidin-5-yl)-5-(3,4,5-trifluorophenyl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(2-chloropyridin-4-yl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(3-(pyridazin-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile.

Another embodiment of the invention is5-(3-fluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(pyridazin-4-yl)-5-(3,4,5-trifluorophenyl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(3,5-difluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(4-fluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(pyridazin-4-yl)-5-(pyrimidin-5-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(pyridazin-4-yl)-5-(2,3,6-trifluorophenyl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(pyridazin-4-yl)-5-(2,3,4-trifluorophenyl)-1,2,4-oxadiazole.

Another embodiment of the invention isN,N-dimethyl-N′-(4-(3-(pyridazin-4-yl)-1,2,4-oxadiazol-5-yl)phenylsulfonyl)formimidamide.

Another embodiment of the invention is5-(3,4-difluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(3,4-difluorophenyl)-5-(pyrimidin-5-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(pyrimidin-5-yl)-5-(2,3,4-trifluorophenyl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(pyrimidin-5-yl)-5-(2,3,6-trifluorophenyl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(pyrimidin-5-yl)-5-(2,3,4,5-tetrafluorophenyl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(pyrimidin-5-yl)-5-(2,3,6-trifluorophenyl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(pyrimidin-5-yl)-5-(2,3,4,5-tetrafluorophenyl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(imidazo[1,5-a]pyridin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(1H-indol-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(2,7-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(2-methylbenzofuran-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(benzo[d][1,2,3]thiadiazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(1H-benzo[d]imidazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(benzo[d]thiazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(pyridin-3-yl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(1H-indol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(benzofuran-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(1-methyl-1H-benzo[d]imidazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(imidazo[1,2-a]pyridin-6-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(6-chloropyridin-3-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(6-fluoropyridin-3-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(5-fluoropyridin-3-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(1H-indazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2(3H)-one.

Another embodiment of the invention is5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazole-2(3H)-thione.

Another embodiment of the invention is1,3-dimethyl-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one.

Another embodiment of the invention is6-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2(3H)-one.

Another embodiment of the invention is5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one.

Another embodiment of the invention is6-(3-(Pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2-amine.

Another embodiment of the invention is6-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazole.

Another embodiment of the invention is5-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzo[d]oxazol-2(3H)-one.

Another embodiment of the invention is5-(5-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzo[d]oxazol-2(3H)-one.

Another embodiment of the invention is5-(benzo[d][1,3]dioxol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(Pyridin-3-yl)-5-(pyrimidin-5-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is5-(Pyridazin-4-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole.

Another embodiment of the invention is3-(3,4-difluorophenyl)-5-(pyrimidin-5-yl)-1,2,4-oxadiazole.

Compound names are assigned by using Struct=Name naming algorithm, whichis part of the CHEMDRAW® ULTRA v. 9.0.7 software suite.

Geometric isomers can exist in the present compounds. The inventioncontemplates the various geometric isomers and mixtures thereofresulting from the disposition of substituents around a carbon-carbondouble bond, a carbon nitrogen double bond, a cycloalkyl group, or aheterocycloalkyl group. Substituents around a carbon-carbon orcarbon-nitrogen double bond are designated as being of Z or Econfiguration and substituents around a cycloalkyl or heterocycloalkylare designated as being of cis or trans configuration.

Within the present invention it is to be understood that compoundsdisclosed herein can exhibit the phenomenon of tautomerism. Thus, whenthe formulae drawings within this specification represent one of thepossible tautomeric or stereoisomeric forms, it is to be understood thatthe invention encompasses any tautomeric or stereoisomeric form, andmixtures thereof, and is not to be limited merely to any one tautomericor stereoisomeric form utilized within the naming of the compounds orformulae drawings.

Preparation of Compounds

Preparation of Compounds Suitable for the Composition of the Inventioncan be understood in connection with the following synthetic schemes andexamples, which illustrate a means by which the compounds can beprepared. Methods for preparing suitable nicotinic acetylcholinereceptor ligands and suitable nicotinic acetylcholine subtype α4β2allosteric modulators are readily available in the literature. Suitablecompounds can be prepared by conventional methods for chemical synthesiswith readily available starting materials. Nicotinic acetylcholinereceptor ligands and nicotinic acetylcholine subtype α4β2 allostericmodulators also may be commercially available.

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are: butyllithium (BuLi),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),ethyl acetate (EtOAc), ethanol (EtOH), 1-hydroxybenzotriazole (HOBT),high-pressure liquid chromatography (HPLC), tetrahydrofuran (THF),triethylamine (NEt₃ or Et₃N), triphenylphosphine (PPh₃),polymer-supported triphenylphosphine (PS-PPh₃), methanol (MeOH),dimethylsulfoxide (DMSO), trifluoroacetic acid (TFA), palladium acetate(Pd(OAc)₂), acetate (OAc), tris(dibenzylidineacetone) palladium (0)(Pd₂(dba)₃), 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)(PdCl₂(dppf)), Dulbecco's Modified Eagle's Medium (DMEM), fetal bovineserum (FBS), N-methyl-D-glucamine (NMDG), and4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES).

Oxadiazole derivatives suitable for the composition of the invention canbe prepared according to conventional methods. Some suitable methods forpreparing such oxadiazole derivatives are provided in the Schemes andExamples below. However, such further illustration is intended only forreference and is not intended in any way to limit the scope of theinvention.

As shown in Scheme 1, compounds of formula (II), wherein Ar² and Ar³,are as defined in formula (II) above, can be prepared as described inScheme 1. Aryl or heteroaryl compounds of general formula (1), can betreated with formula (2) with heat in a solvent including, but notlimited to pyridine, to provide of general formula (II).

As shown in Scheme 2, compounds of formula (4) can be reacted withcompounds of formula (5) in POCl₃ at temperatures from 40-100° C. over1-24 hours to provide compounds of formula (6); wherein R³ is Ar¹ and R⁴is Y, or R³ is Y and R⁴ is Ar¹. Alternatively, compounds of formula (4)can be reacted with compounds of formula (5) in the presence oftriphenylphosphine, which may optionally be polymer bound, andtrichloroacetonitrile in acetonitrile. The mixture may be heated in amicrowave oven at 100-175° C. for 5-30 minutes as described by Wang, Y.;Sauer, D. R.; Djuric, S. W. Tetrahedron. Lett. 2006, 47, 105-108.Another alternative includes combining compounds of formula (4) andcompounds of formula (5) in a solvent such as methylene chloride in thepresence of 2-chloro-1,3-dimethylimidazolinium chloride and a base suchas triethylamine at 15-35° C. for 10-120 hours as described by Isobe,T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6989-6992.

As shown in Scheme 3, compounds of formula (1) can be reacted with urea(7) in a solvent such as dichloromethane in the presence of a base suchas triethylamine at 25-40° C. for 1-12 hours to provide compounds offormula (8) as described in Sobol, E.; Bialer, M.; Yagen, B. J. Med.Chem. 2004, 47, 4316-4326. Alternatively, compounds of formula (1) and(7) may be combined in pyridine at 20-110° C. for 1-24 hours to providecompounds of formula (8). Compounds of formula (8) can be treated withPOCl₃ at 25-100° C. for 1-24 hours to provide compounds of formula (9).Compounds of formula (9) can be reacted with H—X—Y in the presence of abase such as lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, potassiumt-butoxide, sodium hydride, potassium carbonate, sodium carbonate,cesium or carbonate in a solvent such as tetrahydrofuran,1-methyl-2-pyrrolidinone, dimethyl sulfoxide, or acetonitrile attemperatures from −20° C. to 150° C. over 1-48 hours to providecompounds of formula (I).

As shown in Scheme 4, compounds of formula (II), wherein Ar² and Ar³,are as defined in formula (II), can be prepared as described in Scheme4. Aryl or heteroaryl compounds of general formula (10), can be treatedwith compounds of formula (2) in the presence of a coupling agent suchas N-(3-methylaminopropyl)-N′-ethylcarbodiimide hydrochloride and1-hydroxybenzotriazole with heat in a solvent including, but not limitedto dimethylformamide, to provide compounds of general formula (II).

As shown in Scheme 5, compounds of formula (II), wherein Ar² and Ar³,are as previously defined, can be prepared as described in Scheme 5.Compounds of formula (13), which can be either obtained from acommercial source or prepared from compounds of formula (11). Amides offormula (12) can be prepared by reacting compounds of formula (11) withammonium hydroxide. Subsequent dehydration of compound of formula (12)with a dehydrating agent, such as but not limited to phosphorousoxychloride or trifluoroacetic anhydride (TFAA)/triethylamine providecompounds of formula (13). Compounds of formula (13) can be reacted withhydroxylamine to give compounds of formula (2). Compounds of formula (2)react with an aromatic carboxylic acids of formula (10) in the presenceof a coupling agent, such as but not limited toN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(EDC)/1-hydroxybenzotriazole (HOBT), in dimethylformamide at 80-120° C.to give compounds of formula (II). Alternatively, compounds of formula(II) can also be prepared by heating a mixture of compounds of formula(2) and compound of formula (1) which can be obtained from either acommercial source or by the treatment of compound of formula (10) with achlorinating agent, such as oxalyl chloride or thionyl chloride, in asolvent such as but not limited to pyridine or THF at 60-110° C.

Compounds of formula (III), wherein Ar² and Ar³ are as defined informulas (II), can be prepared as described in Scheme 6. Compounds offormula (14) can be first reacted with hydroxylamine at ambienttemperature and then treated with bromine in dichloromethane attemperatures from 0-20° C. to provide compounds of formula (15) asdescribed by Berrier, J. V. and Umarvadia, A. S. in EP0979814. Thecompounds of formula (15) reacts with compounds of formula (13) in thepresence a base, such as but not limited to triethylamine, Na₂CO₃ andK₂CO₃, in a solvent, such as toluene, at temperature ranging 80-110° C.over 10-40 hours to provide compounds of formula (16) as described byHumphrey, G. R.; Wright, S. H. B. in J. Heterocyclic Chem. (1989, 26,23-24). Compounds of formula (17), wherein halo is chloro, bromo oriodo, when treated with an organoboranes of formula (18) or ditincompounds of formulas (19), such as bis(pinacolato)diboron orhexmethlyditin, respectively, wherein R^(m) or R^(n) are hydrogen, alkylor aryl, in the presence of a palladium catalyst, such as, but notlimited to Pd(OAc)₂, PdCl₂(PPh₃)₂, Pd(PPh₃)₄, PdCl₂(dppf), Pd₂(dba)₃provide the corresponding tin or boronic acid or boronic esters offormula (20), wherein M is —Sn—(R^(n))₃ or —B(OR^(m))₂. Compounds offormula (16) can be reacted with compounds of formula (20) in thepresence of a palladium catalyst, such as, but not limited to Pd(OAc)₂,PdCl₂(PPh₃)₂, Pd(PPh₃)₄, PdCl₂(dppf), Pd₂(dba)₃, and a base, such as butnot limited to CsF, Na₂CO₃, K₂CO₃ and K₃PO₄, will provide compounds offormula (III). Alternatively, compounds of formula (16) when treatedwith organoboranes of formula (18) or ditin compounds of formulas (19),such as bis(pinacolato)diboron or hexmethlyditin, respectively, in thepresence of a palladium catalyst provide organotin compounds,organoboronic acids or organoboronic esters compounds of formula (23),wherein M is —Sn—(R^(n))₃ or —B(OR^(m))₂. Compounds of formula (23) canalso be prepared by the initial treatment of compounds of formula (16)with s-BuLi at temperature ranging from −90° C. to −60° C. and thenreaction with a boronic ester of formula (21) or an organotin compoundof formula (22). Compounds of formula (23) can be reacted with compoundsof formula (17) in the presence of a palladium catalyst, such as, butnot limited to Pd(OAc)₂, PdCl₂(PPh₃)₂, Pd(PPh₃)₄, PdCl₂(dppf),Pd₂(dba)₃, and a base, such as but not limited to CsF, Na₂CO₃, K₂CO₃ andK₃PO₄ to provide compounds of formula (III).

The compounds of formula (III), wherein Ar² and Ar³ are as previouslydefined can be prepared as shown in Scheme 7. Compounds of formula (24),where in Ar² is defined in formulas (II) and (III), when treated withtrimethyloxonium tetrafluoroborate in dichloromethane provide compoundsof formula (25) as described by McClelland, R. A. in J. Am. Chem. Soc.(1978, 100, 1844-1849). Compounds of formula (25) can be reacted withcompounds of formula (12), wherein Ar³ is defined in formulas (II) and(III), at temperature ranging from 80-140° C. over 1-6 hours to givecompounds of formula (26). Compounds of formula (26) react withhydroxylamine in acetic acid at room temperature to 90° C. to providethe compounds of formula (III) as described by Lin, Y.-I., et al., J.Org. Chem., 44, 4160-4164, 1979.

In addition, compounds of formula (II) and (III), wherein at least oneof Ar¹ and Ar² is a N-containing heteroaryl, can be converted tocompounds with N⁺—O⁻ by treatment with an oxidizing agent. Examples ofthe oxidizing agent include, but are not limited to aqueous hydrogenperoxide and m-chloroperbenzoic acid. The reaction is generallyperformed in a solvent such as, but not limited to acetonitrile, water,dichloromethane, acetone or a mixture thereof, preferably a mixture ofacetonitrile and water, at a temperature from about 0° C. to about 80°C., for a period of about 1 hour to about 4 days.

The compounds and intermediates of the invention may be isolated andpurified by methods well-known to those skilled in the art of organicsynthesis. Examples of conventional methods for isolating and purifyingcompounds can include, but are not limited to, chromatography on solidsupports such as silica gel, alumina, or silica derivatized withalkylsilane groups, by recrystallization at high or low temperature withan optional pretreatment with activated carbon, thin-layerchromatography, distillation at various pressures, sublimation undervacuum, and trituration, as described for instance in “Vogel's Textbookof Practical Organic Chemistry”, 5th edition (1989), by Furniss et al.,pub. Longman Scientific & Technical, Essex CM20 2JE, England.

Compounds and processes suitable for preparing compounds for thecomposition of the invention will be better understood in connectionwith the following Examples, which are intended as an illustration ofand not a limitation upon the scope of the invention.

Preparation of 2,5-Disubstituted-1,3,4-Oxadiazole Derivatives

Suitable 2,5-disubstituted-1,3,4-oxadiazole derivatives were preparedusing readily available starting materials. For example, InternationalPublication WO 02/100826, published Dec. 19, 2002, describes thepreparation of some oxadiazole derivatives. However, Compounds offormula (I) also can be prepared according to the following generalmethods.

Method A: A carboxylic acid (0.5 mmol) and an acyl hydrazide (0.5 mmol)were combined in POCl₃ (2 mL) and stirred at 80-90° C. for 2-4 hours.The reaction mixture was then cooled down to ambient temperature andpoured into ice water (10-20 g) and basified with saturated aqueoussodium carbonate to pH=8-9. The resultant precipitate was filtered,dried and purified with chromatography on silica gel to provide thecorresponding 2,5-disubstituted-1,3,4-oxadiazole. The free base was thendissolved in EtOAc (5-10 mL) and treated with HCl (Aldrich, 4 M indioxane, 2-3 eq.) at ambient temperature for 5-10 hours. The precipitatewas filtered and dried to provide the corresponding2,5-disubstituted-1,3,4-oxadiazole hydrochloric acid salt.

Method B: A Smith Process vial (0.5-2 ml) was charged with a stir bar.To the vessel were added a carboxylic acid (0.1 mmol), nicotinichydrazide (Aldrich, 13.7 mg, 0.1 mmol), PS-PPh₃ (Fluka, 2.2 mmol/g, 136mg, 0.3 mmol) and Acetonitrile (anhydrous, Aldrich, 2 mL), followed byCCl₃CN (Aldrich, 28.8 mg, 0.20 mmol). The reaction vessel was sealed andheated to 150° C. for 15 minutes using an Emrys™ Optimizer Microwave(Personal Chemistry, www.personalchemistry.com). After cooling, thereaction vessel was uncapped and the resin was removed by filtration.The mixture was purified by preparative HPLC [Waters, column: Nova-Pak®HR C18 6 μm 60 Å Prep-Pak® (25 mm×100 mm), solvent: acetonitrile/water(v. 1% TFA), 5/95 to 95/5, flow rate of 40 mL/minute. Fractions werecollected based upon UV signal threshold, and selected fractions weresubsequently analyzed by flow injection analysis mass spectrometry usingpositive APCI ionization on a Finnigan LCQ using 70:30 methanol:10 mMNH₄OH(aq) at a flow rate of 0.8 mL/minute.]. Some mixtures were purifiedby an alternative preparative HPLC method [Waters, column: Sunfire OBDC8 5 μm (30 mm×75 mm); solvent: acetonitrile/10 mM aqueous ammoniumacetate, 10/90 to 100/0; flow rate of 50 mL/minute]. Fractions werecollected based upon target mass signal threshold, and selectedfractions were subsequently analyzed by flow injection analysis massspectrometry using the previously described method.

Preparation of 2,5-Disubstituted-1,24-Oxadiazole Derivatives

Suitable 2,5-disubstituted-1,2,4-oxadiazole derivatives were preparedusing readily available starting materials. For example, InternationalPublication WO 02/100826, published Dec. 19, 2002, describes thepreparation of some oxadiazole derivatives. However, compounds offormula (II) and (III) also can be prepared according to the followinggeneral methods.

Method C: To a solution of an aryl or heteroaryl carboxylic acid (1.0mmol) in dimethylformamide (anhydrous, 5 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)(Aldrich, 192 mg, 1.00 mmol) and 1-hydroxybenzotriazole (HOBt) hydrate(Fluka, 153 mg, 1.00 mmol). The mixture was stirred at ambienttemperature for 20 minutes. N′-Hydroxy aryl or heteroarylcarboximidamide (1.0 mmol) was added and the mixture was stirred for6-10 hours, and then warmed to 140° C. for 2-4 hours. The reaction wascooled to ambient temperature and triturated with water (10 mL). Theprecipitate was filtered and dried under vacuum to give the titledcompound. When the reaction mixture failed to give a precipitate, thereaction mixture was extracted with EtOAc (3×30 mL). The combinedextracts were concentrated and the residue was purified withchromatography (SiO₂, hexane/EtOAc) or preparative HPLC [Waters, column:Xbridge™ Prep C18 5 μm, OBD 30×100 mm, solvent: acetonitrile/water(pH=10, prepared with NH₄HCO₃/NH₃.H₂O) or acetonitrile/water (v/v 0.1%TFA), 5/95 to 95/5, flow rate of 40 mL/minute. Fractions were collectedbased upon UV signal threshold.].

Method D: To a solution of N′-Hydroxy aryl or heteroaryl carboximidamide(1.0 mmol) in pyridine (5 mL) was added an aryl or heteroaryl carbonylchloride (1.0 mmol). The mixture was then stirred at the temperatureranging from 80-100° C. for 2-10 hours. The reaction was cooled toambient temperature and triturated with water (10 mL). The precipitatewas filtered and dried under vacuum to give the titled compound. Whenthe reaction mixture failed to give a precipitate, the reaction mixturewas extracted with EtOAc (3×30 mL). The combined extracts wereconcentrated and the residue was purified with chromatography (SiO₂,hexane/EtOAc) or preparative HPLC [Waters, column: Xbridge™ Prep C18 5μm, OBD 30×100 mm, solvent: acetonitrile/water (pH=10) oracetonitrile/water (v/v 0.1% TFA), 5/95 to 95/5, flow rate of 40mL/minute. Fractions were collected based upon UV signal threshold.].

EXAMPLE 1 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile

3-Pyridylamideoxime (Aldrich, 5.5 g, 40 mmol) was dissolved in 60 mL ofpyridine and 3-cyanobenzoyl chloride (Aldrich, 6.6 g, 40 mmol) wasadded. The reaction mixture was heated to reflux for 4 hours and thencooled to room temperature. The solution was poured into water (500 mL),filtered, and the solid were collected and dried under vacuum. ¹H NMR(300 MHz, CD₃OD) δ ppm 7.87 (td, J=8.0, 0.7 Hz, 1H), 8.10 (dt, J=8.1,1.4 Hz, 1H), 8.23 (ddd, J=8.1, 5.6, 0.8 Hz, 1H), 8.56 (ddd, J=8.0, 1.7,1.2 Hz, 1H), 8.64 (td, J=1.7, 0.7 Hz, 1H), 9.04 (dd, J=5.4, 1.0 Hz, 1H),9.23 (dt, J=8.1, 1.7 Hz, 1H), 9.57 (d, J=1.7 Hz, 1H); MS (+ESI) m/z 249(M+H)⁺.

EXAMPLE 2 3,5-di(pyridin-3-yl)-1,2,4-oxadiazole

3-Pyridylamideoxime (5.5 g, 40 mmol) was dissolved in 60 mL of pyridineand nicotinoyl chloride hydrochloride (7.2 g, 40 mmol) was added. Thereaction mixture was heated to reflux for 4 hours and then cooled toroom temperature. The solution was poured into water (500 mL), basified,filtered, and the solid was collected and dried under vacuum. ¹H NMR(300 MHz, DMSO-d₆) δ 7.75-7.65 (m, 2H), 8.49-8.45 (m, 1H), 8.60-8.57 (m,1H), 8.84-8.82 (dd, J=1.7 Hz, 1H), 8.92-8.90 (dd, J=1.7 Hz, 1H), 9.28(m, 1H), 9.37 (m, 1H) ppm; MS (DCI/NH₃) m/z 225 (M+H)⁺.

EXAMPLE 3 3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile EXAMPLE3A 3-Cyano-N′-hydroxybenzimidamide

Hydroxylamine (Aldrich, 7.65 g, 100 mmol) in ethanol (100 mL) wastreated with 10 N sodium hydroxide (10 mL, 100 mmol). To this solution,isophthalonitrile (Aldrich, 12.8 g, 100 mmol) in 100 mL ethanol wasadded. The reaction mixture was heated to reflux for 3 hours and thencooled to room temperature. The solvent was removed under vacuum and theresidue was purified with flash column chromatography (5%methanol/dichloromethane) to provide the titled compound. ¹H NMR (300MHz, DMSO-d₆) δ 5.98 (bs, 2H), 7.59 (t, J=7.4 Hz, 1H), 8.06-8.0 (m, 2H),9.89 (s, 1H) ppm; MS (DCI/NH₃) m/z 162 (M+H)⁺.

EXAMPLE 3B 3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile

3-Cyano-N′-hydroxybenzimidamide (0.322 g, 1 mmol) was dissolved inpyridine (10 mL) and nicotinoyl chloride (Aldrich, 0.141 g, 1 mmol) wasadded. The reaction mixture was heated to reflux for 3 hours and cooledto room temperature. The cooled reaction mixture was quenched with water(25 mL) and filtered. The solid was further purified with flash columnchromatography (5% methanol/dichloromethane) to give the titledcompound. ¹H NMR (300 MHz, DMSO-d₆) δ 7.75-7.71 (dd, J=5.7, 4.1 Hz, 1H),7.85 (t, J=7.8 Hz, 1H), 8.15-8.12 (d, J=7.8 Hz, 1H) 8.44-8.42 (m, 1H),8.50 (m, 1H), 8.60-8.56 (m, 1H), 8.93-8.91 (dd, J=1.7 Hz, 1H), 9.37-9.38(d, J=1.7 Hz, 1H) ppm; MS (DCI/NH₃) m/z 249 (M+H)⁺.

EXAMPLE 4 3-(5-(6-fluoropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrileEXAMPLE 4A 3-Cyano-N′-hydroxybenzimidamide

Hydroxylamine (Aldrich, 7.65 g, 100 mmol) in ethanol (100 mL) wastreated with 10 N NaOH (10 mL, 100 mmol). To this solution,isophthalonitrile (Aldrich, 12.8 g, 100 mmol) in 100 mL of ethanol wasadded. The reaction mixture was heated to reflux for 3 hours and thencooled to room temperature. The solvent was removed under vacuum and theresidue was purified with flash column chromatography (5%methanol/dichloromethane) to give the titled product. ¹H NMR (300 MHz,DMSO-d₆) δ 5.98 (bs, 2H), 7.59 (t, J=7.4 Hz, 1H), 8.06-8.0 (m, 2H), 9.89(s, 1H) ppm; MS (DCI/NH₃) m/z 162 (M+H)⁺.

EXAMPLE 4B 3-(5-(6-fluoropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile

3-Cyano-N′-hydroxybenzimidamide (0.322 g, 1 mmol) was dissolved inpyridine 10 mL and 6-fluoronicotinoyl chloride (Frontier Scientific,0.160 g, 1 mmol) was added. The reaction mixture was heated to refluxfor 3 hours and then cooled to room temperature. The cooled reactionmixture was quenched with water (25 mL) and filtered. The solid wasfurther purified with flash column chromatography (5%methanol/dichloromethane) to give the titled product. ¹H NMR (300 MHz,DMSO-d₆) δ 7.56-7.52 (m, 1H), 7.85 (t, J=7.9 Hz, 1H), 8.15-8.12 (m, 1H),8.43-8.41 (m, 1H), 8.49 (m, 1H), 8.8-8.74 (m, 1H), 9.11-9.0 (m, 1H) ppm;MS (DCI/NH₃) m/z 267 (M+H)⁺.

EXAMPLE 5 5-(5-bromopyridin-3-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 1using N′-hydroxynicotinimidamide (Aldrich) and 5-bromonicotinoylchloride (Alfa). ¹H NMR (300 MHz, DMSO-d₆) δ 8.65-8.69 (m, 1H),8.45-8.49 (m, 1H), 8.79 (t, J=1.7 Hz, 1H), 8.84 (dd, J=1.7, 2.0 Hz, 1H),9.07 (d, J=2 Hz, 1H), 9.28-9.29 (m, 1H), 9.34 (d, J=1.7 Hz, 1H) ppm; MS(DCI/NH₃) m/z 303 (M+H)⁺.

EXAMPLE 63-(pyridin-3-yl)-5-(3-(trifluoromethylsulfonyl)phenyl)-1,2,4-oxadiazoleEXAMPLE 6A 3-(trifluoromethylsulfonyl)benzoic acid

A solution of 3-(trifluoromethylthio)benzoic acid (222 mg, 1 mmol) indichloromethane (10 mL) was stirred with chromium(VI) oxide (Aldrich,2.0 mmol) at ambient temperature for 12 hours. The title compound wasobtained by directly loading the reaction mixture onto a silica gelcolumn and eluting with dichloromethane/methanol (9:1). ¹H NMR (300 MHz,DMSO-d₆) δ 8.8 (s, 1H), 8.28 (m, 1H), 8.05 (m, 1H), 7.9 (m, 1H) ppm; MS(DCI/NH₃) m/z 255 (M+H)⁺.

EXAMPLE 6B 3-(trifluoromethylsulfonyl)benzoyl chloride

A solution of the product of Example 6A (198 mg, 0.8 mmol) indichloromethane (10 mL) was stirred with oxalyl dichloride (Aldrich, 2.0mmol) and 1 drop of dimethylformamide at ambient temperature for 2hours. The title compound was obtained by removing the solvent undervacuum as a yellow oil (250 mg) and the compound was used directly inthe next step.

EXAMPLE 6C3-(pyridin-3-yl)-5-(3-(trifluoromethylsulfonyl)phenyl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 1using N-hydroxynicotinimidamide (Aldrich) and the compound of Example6B. ¹H NMR (300 MHz, DMSO-d₆) δ 7.73 (dd, J=4, 5.0 Hz, 1H), 7.85 (t, J=8Hz, 1H), 8.13 (m, 1H), 8.43 (m, 1H) 8.5 (m, 1H), 8.6 (m, 1H), 8.92 (m,1H), 9.37 (m, 1H) ppm; MS (DCI/NH₃) m/z 356 (M+H)⁺.

EXAMPLE 7 3-(3-(6-methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrileEXAMPLE 7A N′-hydroxy-6-methylnicotinimidamide

Hydroxylamine (Aldrich, 0.765 g, 10 mmol) in ethanol (10 mL) was treatedwith a solution 6-methylnicotinonitrile (Aldrich, 12.8 g, 100 mmol) inethanol (10 mL). The reaction mixture was heated to reflux for 3 hoursand then cooled to room temperature. The solvent was removed undervacuum and the residue was purified with flash column chromatography (5%methanol/dichloromethane) give the titled compound. ¹H NMR (300 MHz,DMSO-d₆) δ 2.2 (s, 3H), 6.02 (bs, 2H), 7.59 (m, 1H), 8.06-8.0 (m, 2H),10.2 (s, 1H) ppm; MS (DCI/NH₃) m/z 152 (M+H)⁺.

EXAMPLE 7B 3-(3-(6-methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile

The titled compound was prepared according to the procedure of Example 1using N′-hydroxynicotinimidamide (Example 7A) and 3-cyanobenzoylchloride (Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 2.59 (s, 3H), 7.52 (d,J=8.1 Hz, 1H), 7.39 (t, J=8.5 Hz, 1H), 8.23-8.21 (m, 1H), 8.36-8.32 (m,1H), 8.53-8.49 (m, 1H), 8.64 (m, 1H), 9.14 (m, 1H), ppm; MS (DCI/NH₃)m/z 263 (M+H)⁺.

EXAMPLE 85-(5-(pyrrol-1-yl)pyridin-3-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

To a solution of 5-(1H-pyrrol-1-yl)nicotinic acid (Maybridge, 188 mg,1.00 mmol) in dimethylformamide (anhydrous, 5 mL) was addedN-(3-methylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)(Aldrich, 192 mg, 1.00 mmol) and 1-hydroxybenzotriazole (HOBT) hydrate(Fluka, 153 mg, 1.00 mmol). The mixture was stirred at ambienttemperature for 20 minutes. N′-Hydroxynicotinimidamide (137 mg, 1.0mmol) was added and the mixture was stirred for 6-10 hours, and thenwarmed to 140° C. for 2-4 hours. The reaction was cooled to ambienttemperature and triturated with water (10 mL). The precipitate wasfiltered and dried under vacuum to give the titled compound. ¹H NMR (300MHz, DMSO-d₆) δ 6.34-6.44 (m, 2H), 7.60-7.82 (m, 3H), 8.50 (dt, J=8.1,1.9 Hz, 1H), 8.71 (dd, J=2.5, 1.9 Hz, 1H), 8.84 (dd, J=4.6, 1.5 Hz, 1H),9.21 (d, J=1.7 Hz, 1H), 9.26 (d, J=2.4 Hz, 1H), 9.31 (d, J=1.7 Hz, 1H)ppm; MS (DCI/NH₃) m/z 290 (M+H)⁺.

EXAMPLE 9 5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)pyridin-3-ol

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 5-hydroxynicotinic acid(Matrix Scientific). ¹H NMR (300 MHz, DMSO-d₆) δ 7.66 (ddd, J=8.0, 4.9,1.0 Hz, 1H), 7.86 (dd, J=2.7, 2.0 Hz, 1H), 8.31-8.55 (m, 2H), 8.83 (s,2H), 9.26 (s, 1H) ppm; MS (DCI/NH₃) m/z 241 (M+H)⁺.

EXAMPLE 10 5-(3,4-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 3,4-difluorobenzoic acid(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.52-7.67 (m, 2H), 8.12 (ddd,J=8.7, 4.3, 1.5 Hz, 1H), 8.19 (ddd, J=10.8, 7.5, 2.0 Hz, 1H), 8.55 (dt,J=8.1, 1.9 Hz, 1H), 8.74 (dd, J=5.1, 1.7 Hz, 1H), 9.29 (dd, J=2.0, 0.7Hz, 1H) ppm; MS (DCI/NH₃) m/z 260 (M+H)⁺.

EXAMPLE 11 5-(2,3-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 2,3-difluorobenzoic acid(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.51-7.67 (m, 2H), 8.08-8.14 (m,1H), 8.18 (ddd, J=10.7, 7.5, 2.0 Hz, 1H), 8.55 (dt, J=8.0, 1.9 Hz, 1H),8.74 (dd, J=5.2, 1.6 Hz, 1H), 9.29 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS(DCI/NH₃) m/z 260 (M+H)⁺.

EXAMPLE 12 5-(pyrazin-2-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and pyrazine-2-carboxylicacid (Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.66 (ddd, J=8.0, 4.9, 1.0 Hz,1H), 8.60 (dt, J=8.0, 1.9 Hz, 1H), 8.77 (dd, J=5.0, 1.8 Hz, 1H),8.86-8.89 (m, 1H), 8.89-8.91 (m, 1H), 9.34 (dd, J=2.4, 0.8 Hz, 1H), 9.56(d, J=1.6 Hz, 1H) ppm; MS (DCI/NH₃) m/z 226 (M+H)⁺.

EXAMPLE 13 5-(3,5-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 3,5-difluorobenzoic acid(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.37 (tt, J=9.0, 2.3 Hz, 1H), 7.65(ddd, J=7.9, 5.0, 1.0 Hz, 1H), 7.82-7.91 (m, 2H), 8.56 (dt, J=7.9, 2.0Hz, 1H), 8.75 (dd, J=4.8, 1.6 Hz, 1H), 9.30 (dd, J=2.0, 0.8 Hz, 1H) ppm;MS (DCI/NH₃) m/z 260 (M+H)⁺.

EXAMPLE 14 5-(2,35-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 2,3,5-trifluorobenzoicacid (Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.55-7.68 (m, 2H), 7.83-7.90(m, 1H), 8.57 (dt, J=8.1, 1.9 Hz, 1H), 8.75 (dd, J=5.1, 1.7 Hz, 1H),9.30 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 278 (M+H)⁺.

EXAMPLE 15 5-(2,4,5-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 2,4,5-trifluorobenzoicacid (Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.55 (td, J=10.3, 6.4 Hz, 1H),7.64 (ddd, J=8.1, 5.0, 0.8 Hz, 1H), 8.23 (ddd, J=10.3, 8.6, 6.4 Hz, 1H),8.56 (dt, J=8.1, 1.9 Hz, 1H), 8.75 (dd, J=5.1, 1.7 Hz, 1H), 9.29 (d,J=1.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z 278 (M+H)⁺.

EXAMPLE 16 5-(2,5-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 2,5-difluorobenzoic acid(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.41-7.56 (m, 2H), 7.65 (ddd,J=7.9, 5.0, 1.0 Hz, 1H), 7.98-8.04 (m, 1H), 8.57 (dt, J=8.0, 1.9 Hz,1H), 8.75 (dd, J=5.2, 1.6 Hz, 1H), 9.31 (dd, J=2.0, 0.8 Hz, 1H); MS(DCI/NH₃) m/z 260 (M+H)⁺.

EXAMPLE 175-(4-chloro-2,5-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and4-chloro-2,5-difluorobenzoic acid (Aldrich). ¹H NMR (300 MHz, CD₃OD) δ7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.73 (dd, J=9.7, 5.9 Hz, 1H), 8.18(dd, J=8.8, 6.1 Hz, 1H), 8.57 (dt, J=8.1, 1.9 Hz, 1H), 8.75 (dd, J=4.7,1.7 Hz, 1H), 9.30 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 294(M+H)⁺.

EXAMPLE 18 5-(5-methylpyrazin-2-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and5-methylpyrazine-2-carboxylic acid (Aldrich). ¹H NMR (300 MHz, CD₃OD) δ2.71 (s, 3H), 7.66 (ddd, J=8.0, 5.1, 0.8 Hz, 1H), 8.59 (dt, J=7.9, 1.8Hz, 1H), 8.74-8.78 (m, 2H), 9.33 (dd, J=2.0, 0.8 Hz, 1H), 9.40 (d, J=1.2Hz, 1H) ppm; MS (DCI/NH₃) m/z 240 (M+H)⁺.

EXAMPLE 19 4-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile

The title compound was prepared according to the procedure of Example 1using N′-hydroxynicotinimidamide (Aldrich) and 4-cyanobenzoyl chloride(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1H),8.02 (d, J=8.8 Hz, 2H), 8.42 (d, J=8.8 Hz, 2H), 8.57 (dt, J=8.1, 1.9 Hz,1H), 8.75 (dd, J=4.7, 1.7 Hz, 1H), 9.31 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS(DCI/NH₃) m/z 249 (M+H)⁺.

EXAMPLE 202,3,6-trifluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and2,4,5-trifluoro-3-hydroxybenzoic acid (Aldrich). ¹H NMR (300 MHz, CD₃OD)δ 7.63-7.76 (m, 2H), 8.44 (dt, J=7.9, 2.0 Hz, 1H), 8.83 (dd, J=4.8, 1.6Hz, 1H), 9.25 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH₃) m/z 294 (M+H)⁺.

EXAMPLE 21 2-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 4-fluoro-3-hydroxybenzoicacid (Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 7.45 (dd, J=11.1, 8.7 Hz,1H), 7.62-7.71 (m, 2H), 7.78 (dd, J=8.3, 2.0 Hz, 1H), 8.43 (dt, J=7.9,1.8 Hz, 1H), 8.82 (dd, J=5.0, 1.8 Hz, 1H), 9.24 (d, J=2.0 Hz, 1H) ppm;MS (DCI/NH₃) m/z 258 (M+H)⁺.

EXAMPLE 22 2-fluoro-4-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 3-fluoro-4-hydroxybenzoicacid (Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.09 (t, J=8.7 Hz, 1H), 7.63(ddd, J=7.9, 5.2, 0.8 Hz, 1H), 7.86-7.93 (m, 2H), 8.53 (dt, J=7.9, 2.0Hz, 1H), 8.72 (dd, J=4.8, 1.6 Hz, 1H), 9.27 (dd, J=2.4, 0.8 Hz, 1H) ppm;MS (DCI/NH₃) m/z 258 (M+H)⁺.

EXAMPLE 23 5-(3-chloro-4-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 3-chloro-4-fluorobenzoicacid (Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.54 (t, J=8.8 Hz, 1H), 7.64(ddd, J=8.1, 5.0, 0.8 Hz, 1H), 8.24 (ddd, J=8.6, 4.6, 2.0 Hz, 1H), 8.39(dd, J=7.0, 2.2 Hz, 1H), 8.55 (dt, J=8.1, 1.9 Hz, 1H), 8.74 (dd, J=4.9,1.5 Hz, 1H), 9.29 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 276(M+H)⁺.

EXAMPLE 24 5-(3,4-dichlorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 3,4-dichlorobenzoic acid(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.64 (ddd, J=8.0, 5.1, 0.8 Hz, 1H),7.82 (d, J=8.3 Hz, 1H), 8.14-8.19 (m, 1H), 8.40 (d, J=2.0 Hz, 1H), 8.56(dt, J=7.9, 2.0 Hz, 1H), 8.75 (dd, J=5.2, 1.6 Hz, 1H), 9.29 (dd, J=2.2,1.0 Hz, 1H) ppm; MS (DCI/NH₃) m/z 292 (M+H)⁺.

EXAMPLE 25 2-nitro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 3-hydroxy-4-nitrobenzoicacid (Maybridge). ¹H NMR (300 MHz, DMSO-d₆) δ 6.51 (d, J=9.1 Hz, 1H),6.92-7.31 (s (broad), 1H), 7.61 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.68 (dd,J=9.1, 2.4 Hz, 1H), 8.40 (dt, J=7.9, 2.0 Hz, 1H), 8.53 (d, J=2.4 Hz,1H), 8.77 (dd, J=4.8, 1.6 Hz, 1H), 9.20 (d, J=1.6 Hz, 1H) ppm; MS(DCI/NH₃) m/z 285 (M+H)⁺.

EXAMPLE 26 5-(2,36-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 2,3,6-trifluorobenzoicacid (Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.26-7.35 (m, J=9.4, 9.4, 3.8,2.0 Hz, 1H), 7.62-7.77 (m, 2H), 8.57 (dt, J=8.0, 1.9 Hz, 1H), 8.76 (dd,J=4.8, 1.6 Hz, 1H), 9.30 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z278 (M+H)⁺.

EXAMPLE 272,2,2-trifluoro-1-(4-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)ethanonetrifluoroacetate

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and4-(2,2,2-trifluoroacetyl)benzoic acid (Aldrich). ¹H NMR (300 MHz, CD₃OD)δ 7.81 (ddd, J=7.9, 5.2, 0.8 Hz, 1H), 7.96 (d, J=8.3 Hz, 2H), 8.28 (d,J=8.7 Hz, 2H), 8.76 (dt, J=8.2, 1.8 Hz, 1H), 8.82 (dd, J=5.2, 1.6 Hz,1H), 9.38 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH₃) m/z 320 (M+H)⁺.

EXAMPLE 28 5-(3-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 3-fluorobenzoic acid(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.43-7.51 (m, J=8.5, 8.5, 2.6, 1.0Hz, 1H), 7.61-7.72 (m, 2H), 7.98 (ddd, J=9.1, 2.6, 1.4 Hz, 1H), 8.08(ddd, J=8.0, 1.3, 1.0 Hz, 1H), 8.56 (dt, J=8.0, 1.9 Hz, 1H), 8.74 (dd,J=5.2, 1.6 Hz, 1H), 9.30 (dd, J=2.0, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z242 (M+H)⁺.

EXAMPLE 29 5-(4-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 4-fluorobenzoic acid(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.39 (t, J=8.9 Hz, 2H), 7.64 (ddd,J=7.9, 4.8, 0.8 Hz, 1H), 8.27-8.35 (m, 2H), 8.55 (ddd, J=8.1, 2.0, 1.8Hz, 1H), 8.74 (dd, J=5.0, 1.8 Hz, 1H), 9.29 (dd, J=2.2, 1.0 Hz, 1H) ppm;MS (DCI/NH₃) m/z 242 (M+H)⁺.

EXAMPLE 30 5-(2-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 2-fluorobenzoic acid(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.38-7.49 (m, 2H), 7.64 (ddd,J=8.0, 4.9, 1.0 Hz, 1H), 7.70-7.79 (m, 1H), 8.28 (td, J=7.5, 1.9 Hz,1H), 8.57 (dt, J=8.1, 1.9 Hz, 1H), 8.74 (dd, J=4.7, 1.7 Hz, 1H), 9.31(dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 242 (M+H)⁺.

EXAMPLE 313-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 3-cyano-5-fluorobenzoicacid (Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.65 (ddd, J=8.0, 5.1, 0.8 Hz,1H), 7.95 (ddd, J=8.1, 2.6, 1.6 Hz, 1H), 8.32 (ddd, J=8.7, 2.6, 1.4 Hz,1H), 8.46 (t, J=1.4 Hz, 1H), 8.58 (ddd, J=8.1, 2.0, 1.8 Hz, 1H), 8.76(dd, J=5.2, 1.6 Hz, 1H), 9.31 (dd, J=2.0, 0.8 Hz, 1H) ppm; MS (DCI/NH₃)m/z 267 (M+H)⁺.

EXAMPLE 32 3-(2,3-difluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazolehydrochloric acid EXAMPLE 32A3-(2,3-difluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 1using 2,3-difluoro-N′-hydroxybenzimidamide (Tyger Scientific) andnicotinoyl chloride hydrochloride (Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ7.42-7.61 (m, 1H), 7.67-7.85 (m, 2H), 7.91-8.04 (m, 1H), 8.57 (dt,J=8.1, 1.9 Hz, 1H), 8.92 (dd, J=4.8, 1.6 Hz, 1H), 9.36 (dd, J=2.4, 0.8Hz, 1H) ppm; MS (DCI/NH₃) m/z 260 (M+H)⁺.

EXAMPLE 32B 3-(2,3-difluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazolehydrochloric acid

A solution of the product of Example 32A (320 mg, 1.23 mmol) in ethylacetate (5 mL) was stirred with hydrochloric acid (Aldrich, 4 M indioxane, 0.5 mL, 2.0 mmol) at ambient temperature for 4 hours. Thetitled compound was collected by filtration and dried under vacuum. ¹HNMR (300 MHz, CD₃OD) δ 7.35-7.46 (m, 1H), 7.49-7.63 (m, 1H), 7.93-8.07(m, 1H), 8.24 (dd, J=8.1, 5.8 Hz, 1H), 9.10 (dd, J=5.8, 1.4 Hz, 1H),9.23 (dt, J=8.0, 1.8 Hz, 1H), 9.66 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH₃)m/z 260 (M+H)⁺.

EXAMPLE 33 3-(3,4-difluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazolehydrochloric acid EXAMPLE 33A3-(3,4-difluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 1using 3,4-difluoro-N′-hydroxybenzimidamide (Tyger Scientific) andnicotinoyl chloride hydrochloride (Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ7.74 (dd, J=7.5, 4.4 Hz, 1H), 8.60 (dt, J=7.8, 2.1 Hz, 1H), 8.93 (dd,J=4.8, 1.6 Hz, 1H), 9.38 (dd, J=2.2, 1.0 Hz, 1H), 9.44-9.48 (m, 3H) ppm;MS (DCI/NH₃) m/z 260 (M+H)⁺.

EXAMPLE 33B 3-(3,4-difluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazolehydrochloric acid

A solution of the product of Example 32A (280 mg, 1.08 mmol) in ethylacetate (5 mL) was stirred with hydrochloric acid (Aldrich, 4 M indioxane, 0.5 mL, 2.0 mmol) at ambient temperature for 4 hours. The titlecompound was collected by filtration and dried under vacuum. ¹H NMR (300MHz, CD₃OD) δ 7.52 (td, J=10.5, 8.3 Hz, 1H), 8.00-8.17 (m, 2H), 8.26(ddd, J=8.1, 5.8, 0.7 Hz, 1H), 9.08-9.14 (m, 1H), 9.22-9.30 (m, 1H),9.66 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH₃) m/z 260 (M+H)⁺.

EXAMPLE 34 5-(2,6-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 2,6-difluorobenzoic acid(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.29 (t, J=8.6 Hz, 2H), 7.65 (ddd,J=8.0, 4.9, 1.0 Hz, 1H), 7.77 (tt, J=8.6, 6.1 Hz, 1H), 8.57 (ddd, J=8.3,1.9, 1.7 Hz, 1H), 8.75 (dd, J=4.7, 1.7 Hz, 1H), 9.30 (dd, J=2.2, 0.8 Hz,1H) ppm; MS (DCI/NH₃) m/z 260 (M+H)⁺.

EXAMPLE 35 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzenesulfonamide

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 3-sulfamoylbenzoic acid(Oakwood). ¹H NMR (300 MHz, CD₃OD) δ 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1H),7.83 (t, J=7.9 Hz, 1H), 8.21 (ddd, J=7.9, 1.8, 1.0 Hz, 1H), 8.45 (dt,J=7.9, 1.4 Hz, 1H), 8.58 (dt, J=8.0, 1.9 Hz, 1H), 8.73-8.77 (m, 2H),9.31 (dd, J=2.2, 1.0 Hz, 1H) ppm; MS (DCI/NH₃) m/z 303 (M+H)⁺.

EXAMPLE 36 5-(2,4-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 2,4-difluorobenzoic acid(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.23-7.36 (m, 2H), 7.64 (ddd,J=8.1, 5.0, 0.8 Hz, 1H), 8.35 (td, J=8.5, 6.4 Hz, 1H), 8.56 (dt, J=7.8,1.9 Hz, 1H), 8.74 (dd, J=5.1, 1.7 Hz, 1H), 9.30 (dd, J=2.2, 0.8 Hz, 1H)ppm; MS (DCI/NH₃) m/z 260 (M+H)⁺.

EXAMPLE 37 5-(2,3,4-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 2,3,4-trifluorobenzoicacid (Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.37-7.48 (m, J=9.3, 9.3, 7.1,2.4 Hz, 1H), 7.64 (ddd, J=7.9, 5.0, 1.0 Hz, 1H), 8.08-8.18 (m, 1H), 8.56(dt, J=8.0, 1.9 Hz, 1H), 8.75 (dd, J=5.0, 1.8 Hz, 1H), 9.30 (dd, J=2.0,0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 278 (M+H)⁺.

EXAMPLE 38 5-(3,4,5-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 3,4,5-trifluorobenzoicacid (Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.64 (ddd, J=8.0, 4.9, 1.0 Hz,1H), 8.01-8.13 (m, 2H), 8.56 (ddd, J=8.1, 1.8, 1.6 Hz, 1H), 8.75 (dd,J=4.8, 1.6 Hz, 1H), 9.29 (dd, J=2.0, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z278 (M+H)⁺.

EXAMPLE 39 5-(4-chloro-3-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 4-chloro-3-fluorobenzoicacid (Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.64 (ddd, J=7.9, 5.0, 1.0 Hz,1H), 7.78 (dd, J=8.3, 7.5 Hz, 1H), 8.07 (ddd, J=8.3, 2.0, 0.8 Hz, 1H),8.12 (dd, J=9.5, 2.0 Hz, 1H), 8.55 (dt, J=7.9, 2.0 Hz, 1H), 8.74 (dd,J=5.0, 1.8 Hz, 1H), 9.28-9.30 (m, 1H) ppm; MS (DCI/NH₃) m/z 276 (M+H)⁺.

EXAMPLE 40 5-(3-nitrophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 3-nitrobenzoyl chloride(Aldrich). ¹H NMR (300 MHz, CDCl₃) δ 7.44-7.55 (m, 1H), 7.82 (t, J=8.3Hz, 1H), 8.43-8.60 (m, 3H), 8.80 (dd, J=4.7, 1.7 Hz, 1H), 9.07-9.13 (m,1H), 9.42 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH₃) m/z 269 (M+H)⁺.

EXAMPLE 415-(3-(methylsulfonyl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 3-(methylsulfonyl)benzoicacid (Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 3.24 (s, 3H), 7.65 (ddd,J=8.0, 4.9, 1.0 Hz, 1H), 7.89-7.96 (m, 1H), 8.28 (ddd, J=8.0, 1.9, 1.0Hz, 1H), 8.55-8.61 (m, 2H), 8.75 (dd, J=5.1, 1.7 Hz, 1H), 8.78 (t, J=1.5Hz, 1H), 9.32 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 302 (M+H)⁺.

EXAMPLE 42 3-(2-chloropyridin-4-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazoleEXAMPLE 42A 2-chloro-N′-hydroxyisonicotinimidamide

A solution of 2-chloroisonicotinonitrile (Aldrich, 0.73 g, 5.27 mmol),and hydroxylamine (Aldrich, 50 wt %, 0.348 g, 5.27 mmol) in methanol (10mL) was heated to reflux and stirred for 1 hour. The volatiles wereremoved under reduced pressure to give the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 6.09 (s, 2H), 7.67 (dd, J=5.4, 1.4 Hz, 1H), 7.73 (d,J=2.0 Hz, 1H), 8.40 (d, J=5.2 Hz, 1H), 10.22 (s, 1H) ppm; MS (DCI/NH₃)m/z 172 (M+H)⁺, 174 (M+H)⁺.

EXAMPLE 42B 3-(2-chloropyridin-4-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 1using the product of Example 42A and nicotinoyl chloride hydrochloride(Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 7.73 (ddd, J=8.0, 4.9, 1.0 Hz,1H), 8.04-8.13 (m, 2H), 8.59 (dt, J=7.9, 2.0 Hz, 1H), 8.71 (d, J=5.2 Hz,1H), 8.92 (dd, J=5.0, 1.8 Hz, 1H), 9.38 (dd, J=2.2, 1.0 Hz, 1H) ppm; MS(DCI/NH₃) m/z 259 (M+H)⁺, 261 (M+H)⁺.

EXAMPLE 43 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzamide

A solution of the product of Example 1 (248 mg, 1 mmol) in THF (10 ml)was stirred with potassium trimethylsilanolate (257 mg, 2.000 mmol) at65° C. for 10 hours. It was then quenched with water (20 mL) and stirredat ambient temperature for 2 hours. The precipitate was filtered anddried under vacuum to give the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ 7.67 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.78 (t, J=7.7 Hz, 1H), 8.23 (dt,J=8.1, 1.4, 1.2 Hz, 1H), 8.30 [s (broad, 2H], 8.36 (dt, J=8.1, 1.3 Hz,1H), 8.48 (dt, J=7.9, 2.0 Hz, 1H), 8.68-8.73 (m, 1H), 8.83 (dd, J=4.8,1.6 Hz, 1H), 9.28 (dd, J=2.2, 1.0 Hz, 1H) ppm; MS (DCI/NH₃) m/z 267(M+H)⁺.

EXAMPLE 44 4-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)pyridin-2(1H)-onehydrochloric acid

A solution of the product of Example 42 (100 mg, 0.39 mmol) inconcentrated hydrochloric acid (Aldrich, 36.5%, 3.0 mL) was heated in anEmry™ Creator microwave to 150° C. at 300 watts for 60 minutes. It wasthen concentrated. The residue was stirred in ethanol/ethyl acetate (v.1/1, 5 mL) at ambient temperature for 1 hour. The title compound wascollected by filtration and dried. ¹H NMR (300 MHz, DMSO-d₆) δ 6.75 (dd,J=6.7, 1.6 Hz, 1H), 7.04 (d, J=1.6 Hz, 1H), 7.61 (d, J=5.9 Hz, 1H),7.67-7.81 (m, 1H), 8.56 (dt, J=8.0, 1.9 Hz, 1H), 8.91 (dd, J=5.0, 1.8Hz, 1H), 9.31-9.40 (m, 1H) ppm; MS (DCI/NH₃) m/z 241 (M+H)⁺.

EXAMPLE 45 tert-butyl 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzoate

N′-Hydroxynicotinimidamide (274 mg, 2.00 mmol) was coupled with3-(tert-butoxycarbonyl)benzoic acid (Aldrich) according to the proceduredescribed in Example 8. ¹H NMR (300 MHz, CD₃OD) δ 1.65 (s, 9H), 7.65(ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.71-7.77 (m, 1H), 8.26 (ddd, J=7.7, 1.8,1.6 Hz, 1H), 8.42-8.46 (m, 1H), 8.57 (dt, J=7.9, 2.0 Hz, 1H), 8.73-8.78(m, 2H), 9.31 (dd, J=2.2, 1.0 Hz, 1H) ppm; MS (DCI/NH₃) m/z 324 (M+H)⁺.

EXAMPLE 46 2-amino-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol

A solution of the product of Example 25 (284 mg, 1 mmol) intetrahydrofuran (10 mL) was stirred with Raney®-nickel (Aldrich, 100 mg)under hydrogen at ambient temperature for 2 hours. The catalyst was thenremoved by filtration and the organic solution concentrated to give thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ 5.67 (s, 2H), 6.74 (d, J=8.1Hz, 1H), 7.41-7.50 (m, 2H), 7.62 (dd, J=8.3, 4.6 Hz, 1H), 8.39 (dt,J=8.2, 1.9, 1.7 Hz, 1H), 8.78 (dd, J=4.7, 1.7 Hz, 1H), 9.20 (d, J=1.7Hz, 1H), 9.74 (s (broad), 1H) ppm; MS (DCI/NH₃) m/z 255 (M+H)⁺.

EXAMPLE 47N,N-dimethyl-4-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine

A solution of the product of Example 42 (100 mg, 0.39 mmol) indimethylformamide (2.0 mL) and ammonium hydroxide (0.5 mL) was sealedand heated to 150° C. in an Emry™ Creator microwave to 150° C. at 300watts for 60 minutes. It was then concentrated. The residue was stirredin water (5 mL) at ambient temperature for 1 hour. The title compoundwas collected by filtration and dried. ¹H NMR (300 MHz, DMSO-d₆) δ 3.12(s, 6H), 7.18 (dd, J=5.2, 1.2 Hz, 1H), 7.21 (t, J=1.2 Hz, 1H), 7.66-7.78(m, 1H), 8.31 (dd, J=4.8, 0.8 Hz, 1H), 8.57 (ddd, J=8.3, 2.0, 1.6 Hz,1H), 8.91 (dd, J=5.0, 1.8 Hz, 1H), 9.35 (d, J=2.4 Hz, 1H) ppm; MS(DCI/NH₃) m/z 268 (M+H)⁺.

EXAMPLE 48 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzoic acid

A solution of the product of Example 45 (180 mg, 0.56 mmol) in methylenechloride (5 mL) was stirred with trifluoroacetic acid (1 mL) at roomtemperature for 4 hours. It was then concentrated and the residue wasstirred in water (15 mL) for 1 hour. The precipitate was collected byfiltration and dried to give the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 7.66 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.83 (t, J=7.5 Hz, 1H),8.28 (ddd, J=8.0, 1.5, 1.2 Hz, 1H), 8.42-8.51 (m, 2H), 8.70 (t, J=1.6Hz, 1H), 8.83 (dd, J=5.0, 1.8 Hz, 1H), 9.28 (dd, J=2.2, 1.0 Hz, 1H) ppm;MS (DCI/NH₃) m/z 268 (M+H)⁺.

EXAMPLE 495-(3-(1H-tetrazol-5-yl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazolehydrochloric acid

A solution of the product of Example 1 (248 mg, 1.0 mmol) in toluene(anhydrous, 10 mL) was stirred with azidotributylstannane (Aldrich, 498mg, 1.50 mmol) at 110° C. for 15 hours. It was then cooled to ambienttemperature and stirred with 5 mL of sodium hydroxide (1 N) at ambienttemperature for 1 hour. The organic solution was separated, the aqueousmixture was acidified to pH=2-3 with hydrochloric acid (10 wt. %) andstirred for 2 hours. The precipitate was collected by filtration anddried to give the title product. ¹H NMR (300 MHz, DMSO-d₆) δ 7.70-7.76(m, 1H), 7.86-7.98 (m, 1H), 8.23 (ddd, J=7.8, 1.7, 1.0 Hz, 0.2H),8.38-8.46 (m, 1.6H), 8.49-8.53 (m, 0.2H), 8.56 (ddd, J=8.1, 1.9 Hz,0.8H), 8.65 (ddd, J=1.7, 0.7 Hz, 0.2H), 8.83-8.92 (m, 2H), 9.30 (dd,J=2.2, 0.8 Hz, 0.2H), 9.33 (dd, J=2.2, 0.8 Hz, 0.8H) ppm; MS (DCI/NH₃)m/z 292 (M+H)⁺.

EXAMPLE 50N,N-diethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzenesulfonamideEXAMPLE 50A 3-(N,N-diethylsulfamoyl)benzoic acid

Diethylamine (Aldrich, 2.5 mL, 24 mmol) was added to a solution of3-(chlorosulfonyl)benzoic acid (Aldrich, 2.0 g, 9.1 mmol) in anhydrousdichloromethane (20 mL) at 0° C. The mixture was then stirred at 0° C.for 2 hours. The volatiles were removed under reduced pressure. Theresidue was treated with aqueous potassium hydrogensulfate (1 M, 10 mL)and then extracted with ethyl acetate (3×50 mL). The combined extractswere dried over magnesium sulfate filtered and then concentrated to givethe title compound. ¹H NMR (300 MHz, CD₃OD) δ 1.13 (t, J=7.1 Hz, 6H),3.22-3.30 (m, 4H), 7.69 (t, J=7.8 Hz, 1H), 8.03 (ddd, J=7.9, 1.9, 1.4Hz, 1H), 8.25 (dt, J=7.8, 1.4 Hz, 1H), 8.40 (t, J=1.7 Hz, 1H) ppm; MS(DCI/NH₃) m/z 275 (M+NH₄)⁺.

EXAMPLE 50BN,N-Diethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzenesulfonamide

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and the product of Example50A. ¹H NMR (300 MHz, CD₃OD) δ 1.17 (t, J=7.1 Hz, 6H), 3.29-3.37 (m,4H), 7.65 (ddd, J=8.1, 5.0, 0.8 Hz, 1H), 7.86 (t, J=7.6 Hz, 1H), 8.14(ddd, J=7.9, 1.8, 1.2 Hz, 1H), 8.48 (dt, J=7.9, 1.5 Hz, 1H), 8.58 (dt,J=8.1, 1.9 Hz, 1H), 8.62 (t, J=1.5 Hz, 1H), 8.75 (dd, J=5.1, 1.7 Hz,1H), 9.31 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 359 (M+H)⁺.

EXAMPLE 512-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 3-cyano-4-fluorobenzoicacid (Aldrich). ¹H NMR (300 MHz, CD₃OD) δ ppm 7.62-7.71 (m, 2H),8.54-8.63 (m, 2H), 8.69 (dd, J=5.9, 2.2 Hz, 1H), 8.75 (dd, J=4.9, 1.5Hz, 1H), 9.30 (dd, J=2.0, 1.0 Hz, 1H); MS (DCI/NH₃) m/z 267 (M+H)⁺.

EXAMPLE 523-(3-(1H-tetrazol-5-yl)phenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazolehydrochloric acid

The title compound was prepared according to the procedure of Example 49using the product of Example 3 and azidotributylstannane (Aldrich). ¹HNMR (300 MHz, DMSO-d₆) δ 7.74 (dd, J=7.3, 5.4 Hz, 1H), 7.87 (t, J=7.7Hz, 1H), 8.25-8.43 (m, 2H), 8.53-8.70 (m, 1H), 8.75-8.85 (m, 1H),8.88-9.00 (m, 1H), 9.32-9.58 (m, 1H) ppm; MS (DCI/NH₃) m/z 292 (M+H)⁺.

EXAMPLE 53 3-(6-chloropyridin-3-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazoleEXAMPLE 53A 6-Chloro-N′-hydroxynicotinimidamide

A solution of 2-chloroisonicotinonitrile (Aldrich, 5.0 g, 36.1 mmol) andhydroxylamine (Aldrich, 50% wt, 2.38 g, 36.0 mmol) in methanol (100 ml)was heated to reflux and stirred for 1 hour. The volatiles were removedunder reduced pressure to give the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 6.03 (s, 2H), 7.54 (d, J=8.7 Hz, 1H), 8.07 (dd, J=8.3, 2.4Hz, 1H), 8.67 (d, J=2.8 Hz, 1H), 9.94 (s, 1H) ppm; MS (DCI/NH₃) m/z 172(M+H)⁺, 189 (M+H)⁺.

EXAMPLE 53B 3-(6-chloropyridin-3-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 1using the product of Example 53A and nicotinoyl chloride hydrochloride(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.62-7.75 (m, 2H), 8.53 (dd, J=8.1,2.4 Hz, 1H), 8.60-8.67 (m, 1H), 8.85 (dd, J=5.1, 1.7 Hz, 1H), 9.14 (dd,J=2.4, 0.7 Hz, 1H), 9.39 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z259 (M+H)⁺, 261 (M+H)⁺.

EXAMPLE 54 5-(6-chloropyridin-3-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 1using N′-hydroxynicotinimidamide (Tyger) and 6-chloronicotinoyl chloride(Aldrich). ¹H NMR (300 MHz, CDCl₃) δ 7.48 (dd, J=7.6, 5.3 Hz, 1H), 7.57(d, J=8.5 Hz, 1H), 8.40-8.48 (m, 2H), 8.80 (dd, J=4.7, 1.7 Hz, 1H), 9.24(d, J=2.4 Hz, 1H), 9.40 (d, J=2.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z 259(M+H)⁺, 261 (M+H)⁺.

EXAMPLE 55 5-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)pyridin-2(1H)-one

A solution of the product of Example 53B (0.10 g, 0.39 mmol) inconcentrated hydrochloric acid (1.0 mL) was heated in a microwave to150° C. at 300 watts for 60 minutes. It was then concentrated underreduced pressure and the residue was purified by chromatography [silicagel, CHCl₃/methanol (with 10% v/v ammonium hydroxide), v. 90/10] toprovide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 6.28-6.73 (m,1H), 7.64-7.74 (m, 1H), 7.98 (dd, J=9.5, 2.7 Hz, 1H), 8.14 (d, J=2.4 Hz,1H), 8.49-8.56 (m, 1H), 8.89 (dd, J=4.7, 1.7 Hz, 1H), 9.32 (d, J=1.4 Hz,1H), 12.17 (s, 1H) ppm; MS (DCI/NH₃) m/z 241 (M+H)⁺, 258 (M+NH₄)⁺.

EXAMPLE 56 5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure of Example 55using the product of Example 54. ¹H NMR (300 MHz, DMSO-d₆) δ 6.55 (d,J=9.2 Hz, 1H), 7.63 (dd, J=7.6, 5.3 Hz, 1H), 8.05 (dd, J=9.8, 2.7 Hz,1H), 8.31-8.47 (m, 2H), 8.80 (d, J=3.4 Hz, 1H), 9.22 (s, 1H), 12.41 (s,1H) ppm; MS (DCI/NH₃) m/z 241 (M+H)⁺, 258 (M+NH₄)⁺.

EXAMPLE 57N-methyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzenesulfonamideEXAMPLE 57A 3-(N-methylsulfamoyl)benzoic acid

The title compound was prepared according to the procedure of Example50A using 3-(chlorosulfonyl)benzoic acid (Aldrich) and methylamine(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 2.54 (s, 3H), 7.70 (t, J=7.8 Hz,1H), 8.02-8.07 (m, 1H), 8.23-8.28 (m, 1H), 8.45 (t, J=1.9 Hz, 1H) ppm;MS (DCI/NH₃) m/z 233 (M+NH₄)⁺.

EXAMPLE 57BN-methyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzenesulfonamide

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and the product of Example57A. ¹H NMR (300 MHz, CD₃OD) δ 2.60 (s, 3H), 7.65 (ddd, J=8.1, 5.0, 0.8Hz, 1H), 7.87 (t, J=8.1 Hz, 1H), 8.15 (ddd, J=8.0, 1.9, 1.0 Hz, 1H),8.48 (ddd, J=7.8, 1.7, 1.0 Hz, 1H), 8.58 (dt, J=8.1, 1.9 Hz, 1H), 8.67(t, J=1.5 Hz, 1H), 8.75 (dd, J=4.7, 1.7 Hz, 1H), 9.31 (dd, J=2.2, 0.8Hz, 1H) ppm; MS (DCI/NH₃) m/z 317 (M+H)⁺.

EXAMPLE 58 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)anilinedihydrochloride EXAMPLE 58A3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)aniline

The title compound was prepared according to the procedure of Example 46using the product of Example 40. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 5.60(s, 2H), 6.84-6.93 (m, 1H), 7.24-7.33 (m, 2H), 7.41 (d, J=1.7 Hz, 1H),7.60-7.67 (m, 1H), 8.38-8.45 (m, 1H), 8.81 (dd, J=5.1, 1.7 Hz, 1H), 9.23(d, J=2.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z 239 (M+H)⁺, 256 (M+NH₄)⁺.

EXAMPLE 58B 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)anilinedihydrochloride

A solution of the product of Example 58A (60 mg, 0.25 mmol) in ethylacetate (2 mL) was stirred with hydrochloric acid (Aldrich, 4 M indioxane, 0.14 mL, 0.55 mmol) at ambient temperature for 4 hours. Thetitle compound was collected by filtration and dried under vacuum. ¹HNMR (300 MHz, DMSO-d₆) δ 7.44 (d, J=7.9 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H),7.80 (dd, J=7.9, 5.2 Hz, 1H), 7.85-7.96 (m, 2H), 8.60 (d, J=7.9 Hz, 1H),8.90 (d, J=4.8 Hz, 1H), 9.31 (s, 1H) ppm; MS (DCI/NH₃) m/z 239 (M+H)⁺,256 (M+NH₄)⁺.

EXAMPLE 59 (3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)methanaminebis(hydrochloric acid)

A solution of the product of Example 62 (120 mg, 0.34 mmol) in ethylacetate (5 mL) was stirred with hydrochloric acid (Aldrich, 4 M indioxane, 0.5 mL, 2.0 mmol) at ambient temperature for 4 hours. Theprecipitate was collected by filtration and dried under vacuum to givethe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 4.21 (q, J=5.9 Hz, 2H),7.65-7.79 (m, 2H), 7.86 (dt, J=8.0, 1.3 Hz, 1H), 8.24 (dt, J=7.7, 1.4Hz, 1H), 8.35-8.45 (m, 3H), 8.48 (dt, J=8.1, 1.9 Hz, 1H), 8.85 (dd,J=4.9, 1.2 Hz, 1H), 9.28 (d, J=1.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z 253(M+H)⁺.

EXAMPLE 60 5-(2-chloropyridin-4-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 1using N′-hydroxynicotinimidamide (Aldrich) and 2-chloroisonicotinoylchloride (Maybridge). ¹H NMR (300 MHz, DMSO-d₆) δ 7.68 (ddd, J=7.9, 4.8,0.8 Hz, 1H), 8.16 (dd, J=5.1, 1.4 Hz, 1H), 8.23 (dd, J=1.5, 0.8 Hz, 1H),8.42-8.54 (m, 1H), 8.77 (dd, J=5.1, 0.7 Hz, 1H), 8.84 (dd, J=4.7, 1.7Hz, 1H), 9.28 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 259 (M+H)⁺,261 (M+H)⁺.

EXAMPLE 61 4-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)pyridin-2(1H)-onehydrochloric acid

The title compound was prepared according to the procedure of Example 44using the product of Example 60. ¹H NMR (300 MHz, DMSO-d₆) δ 6.81 (dd,J=6.6, 1.9 Hz, 1H), 7.09-7.14 (m, 1H), 7.67-7.76 (m, 2H), 8.51 (dt,J=8.0, 1.9, 1.7 Hz, 1H), 8.86 (dd, J=4.9, 1.5 Hz, 1H), 9.28 (d, J=1.4Hz, 1H) ppm; MS (DCI/NH₃) m/z 241 (M+H)⁺.

EXAMPLE 62 tert-butyl3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzylcarbamate

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and3-((tert-butoxycarbonylamino)methyl)benzoic acid (Fluka). ¹H NMR (300MHz, DMSO-d₆) δ 1.42 (s, 9H), 4.27 (d, J=6.1 Hz, 2H), 7.51-7.72 (m, 4H),8.01-8.17 (m, 2H), 8.45 (dt, J=8.1, 1.9 Hz, 1H), 8.82 (dd, J=5.1, 1.7Hz, 1H), 9.26 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 353 (M+H)⁺.

EXAMPLE 63 5-(3-bromophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 1using N′-hydroxynicotinimidamide (Aldrich) and 3-bromobenzoyl chloride(Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 7.60-7.71 (m, 2H), 7.98 (ddd,J=8.1, 2.0, 1.0 Hz, 1H), 8.22 (ddd, J=7.4, 1.6, 1.3 Hz, 1H), 8.35 (t,J=1.8 Hz, 1H), 8.46 (dt, J=7.9, 2.0 Hz, 1H), 8.83 (dd, J=4.8, 1.6 Hz,1H), 9.27 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 302 (M+H)⁺, 304(M+H)⁺.

EXAMPLE 641-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)pyrrolidin-2-one

A solution of the product of Example 63 (200 mg, 0.66 mmol) andpyrrolidin-2-one (Aldrich, 85 mg, 0.99 mmol) in toluene (anhydrous 10mL) was degassed and purged with nitrogen three times, cesium carbonate(Aldrich, 324 mg, 0.993 mmol) andtris(dibenzylideneacetone)dipalladium(0) (Aldrich, 12.1 mg, 0.013 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Aldrich, 23.0 mg, 0.040mmol, xantphos) were added, degassed and purged with nitrogen threetimes. The mixture was then heated to 100° C. and stirred under nitrogenfor 15 hours. It was then cooled to ambient temperature and diluted withethyl acetate (50 mL), washed with brine (2×5 mL), concentrated,purified with chromatography (v. ethyl acetate/hexane=1/1, R_(f)=0.1) togive the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 2.04-2.19 (m, 2H),2.57 (t, J=7.9 Hz, 2H), 3.95 (t, J=6.9 Hz, 2H), 7.60-7.75 (m, 2H),7.84-8.10 (m, 2H), 8.46 (dt, J=7.9, 2.0 Hz, 1H), 8.64 (t, J=2.0 Hz, 1H),8.82 (dd, J=5.0, 1.8 Hz, 1H), 9.26 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS(DCI/NH₃) m/z 307 (M+H)⁺.

EXAMPLE 65 tert-butyl3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenylcarbamate

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and3-(tert-butoxycarbonylamino)benzoic acid (Aldrich). ¹H NMR (300 MHz,CDCl₃) δ 1.56 (s, 9H), 6.71 (s, 1H), 7.39-7.58 (m, 2H), 7.68 (d, J=7.9Hz, 1H), 7.89 (d, J=9.1 Hz, 1H), 8.24 (s, 1H), 8.45 (d, J=7.9 Hz, 1H),8.77 (d, J=4.8 Hz, 1H), 9.40 (s, 1H) ppm; MS (DCI/NH₃) m/z 339 (M+H)⁺,356 (M+NH₄)⁺.

EXAMPLE 66N,N-dimethyl-1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)methanamine,bishydrochloric acid salt

The free base of the title compound was prepared according to theprocedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and3-((dimethylamino)methyl)benzoic acid (Aldrich). A solution of this freebase in ethyl acetate (5 mL) was treated with hydrochloric acid(Aldrich, 0.5 mL, 4M in dioxane) at ambient temperature for 2 hours. Thetitle compound was collected by filtration and dried under vacuum. ¹HNMR (300 MHz, CD₃OD) δ 2.93 (s, 6H), 4.51 (s, 2H), 7.82 (t, J=7.8 Hz,1H), 7.90 (dt, J=7.8, 1.5 Hz, 1H), 8.23 (dd, J=8.0, 5.9 Hz, 1H), 8.42(dt, J=7.7, 1.4 Hz, 1H), 8.49 (t, J=1.5 Hz, 1H), 9.04 (d, J=5.1 Hz, 1H),9.21 (dt, J=8.1, 1.7 Hz, 1H), 9.56 (s, 1H) ppm; MS (DCI/NH₃) m/z 281(M+H)⁺.

EXAMPLE 675-(3-(piperazin-1-yl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazolebis(hydrochloric acid) EXAMPLE 67A tert-butyl4-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)piperazine-1-carboxylate

A solution of the product of Example 63 (200 mg, 0.66 mmol) andtert-butyl piperazine-1-carboxylate (Aldrich, 123 mg, 0.66 mmol) intoluene (anhydrous, 10 mL) was degassed and purged with nitrogen threetimes, sodium t-butoxide (Aldrich, 64 mg, 0.66 mmol) andtris(dibenzylideneacetone)dipalladium(0) (Aldrich, 12.1 mg, 0.013 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Aldrich, 23.0 mg, 0.040mmol, xantphos) were added, degassed and purged with nitrogen threetimes. The mixture was then heated to 100° C. and stirred under nitrogenfor 15 hours. It was then cooled to ambient temperature and diluted withethyl acetate (50 mL), washed with brine (2×5 mL), concentrated,purified with chromatography (v. ethyl acetate/hexane=1/1, R_(f)=0.6) togive the title compound. ¹H NMR (300 MHz, CD₃OD) δ 1.49 (s, 9H),3.25-3.30 (m, 4H), 3.56-3.71 (m, 4H), 7.31 (ddd, J=8.4, 2.6, 0.8 Hz,1H), 7.49 (t, J=8.0 Hz, 1H), 7.64 (ddd, J=8.0, 4.9, 0.7 Hz, 1H), 7.70(dt, J=8.0, 1.1 Hz, 1H), 7.79 (dd, J=2.4, 1.7 Hz, 1H), 8.56 (dt, J=7.9,2.0 Hz, 1H), 8.74 (dd, J=4.9, 1.5 Hz, 1H), 9.29 (dd, J=2.2, 0.8 Hz, 1H)ppm; MS (DCI/NH₃) m/z 408 (M+H)⁺.

EXAMPLE 67B5-(3-(piperazin-1-yl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazolebis(hydrochloric acid)

The title compound was prepared according to the procedure of Example 59using the product of Example 67A. ¹H NMR (300 MHz, CD₃OD) δ 3.40-3.48(m, 4H), 3.54-3.62 (m, 4H), 7.42 (ddd, J=8.3, 2.8, 0.8 Hz, 1H), 7.58 (t,J=8.1 Hz, 1H), 7.78-7.94 (m, 2H), 8.24-8.39 (m, 1H), 9.08 (d, J=5.9 Hz,1H), 9.32 (dt, J=8.3, 1.8 Hz, 1H), 9.59 (d, J=1.6 Hz, 1H) ppm; MS(DCI/NH₃) m/z 308 (M+H)⁺.

EXAMPLE 68 1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)ethanone

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and 3-acetylbenzoic acid(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 2.72 (s, 3H), 7.66 (ddd, J=8.0,4.9, 1.0 Hz, 1H), 7.80 (t, J=8.1 Hz, 1H), 8.31 (ddd, J=8.1, 1.4, 1.2 Hz,1H), 8.47 (ddd, J=8.1, 1.4, 1.2 Hz, 1H), 8.59 (ddd, J=8.1, 2.0, 1.8 Hz,1H), 8.75 (dd, J=5.2, 1.6 Hz, 1H), 8.81 (t, J=1.4 Hz, 1H), 9.32 (dd,J=2.4, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 266 (M+H)⁺.

EXAMPLE 693-(6-chloropyridin-3-yl)-5-(2,3-difluorophenyl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 1using the product of Example 53A and 2,3-difluorobenzoyl chloride(Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 7.41-7.59 (m, 1H), 7.76-7.93 (m,2H), 8.05 (dd, J=7.8, 6.1 Hz, 1H), 8.48 (dd, J=8.3, 2.5 Hz, 1H), 9.08(d, J=2.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z 294 (M+H)⁺, 296 (M+H)⁺.

EXAMPLE 703-(6-chloropyridin-3-yl)-5-(3,4-difluorophenyl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 1using the product of Example 53A and 3,4-difluorobenzoyl chloride(Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.70-7.83 (m, 2H), 8.03-8.15(m, 1H), 8.22-8.36 (m, 1H), 8.48 (dd, J=8.1, 2.4 Hz, 1H), 9.08 (d, J=2.4Hz, 1H) ppm; MS (DCI/NH₃) m/z 294 (M+H)⁺, 296 (M+H)⁺.

EXAMPLE 71(R)-3-(pyridin-3-yl)-5-(3-(pyrrolidin-2-yl)phenyl)-1,2,4-oxadiazolebis(hydrochloric acid) EXAMPLE 71A (R)-tert-butyl2-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)pyrrolidine-1-carboxylate

Under nitrogen, to a solution of tert-butyl pyrrolidine-1-carboxylate(Aldrich, 0.52 g, 3.00 mmol) and (−)-sparteine (Aldrich, 0.69 g, 3.0mmol) in t-butyl methyl ether (Aldrich, anhydrous, 10 mL) was addedsec-butyllithium (Aldrich, 1.4 M in cyclohexane, 2.2 mL, 3.1 mmol) at−78° C. After the completion of the addition, it was stirred at −78° C.for 3 hours. Zinc chloride (Aldrich, 1 M in diethyl ether, 2.0 mL, 2.0mmol) was then added slowly and the resultant solution was stirred at−78° C. for additional 30 minutes and then warmed up to ambienttemperature, stirred for another 30 minutes at room temperature beforethe addition of a solution of the product of the Example 63 (0.30 g, 1.0mmol) in tetrahydrofuran (anhydrous, 5.0 mL) andbis(tri-t-butylphosphine)palladium(0) (Strem, 10.2 mg, 0.02 mmol). Themixture was stirred at ambient temperature for 15 hours and quenchedwith ammonium hydroxide (5 mL). The mixture was extracted with ethylacetate (3×20 mL). The combined extracts were concentrated and purifiedby chromatography (v. hexanes/ethyl acetate=1/1, R_(f)=0.5) to give thetitle compound. ¹H NMR (300 MHz, CD₃OD) δ 1.19 (s (broad), 6H), 1.48 (s(broad), 3H), 1.83-2.00 (m, 2H), 2.37-2.55 (m, J=8.1, 8.1 Hz, 1H),3.57-3.72 (m, 2H), 4.90-5.14 (m, 1H), 7.47-7.73 (m, 3H), 8.00-8.25 (m,2H), 8.56 (dt, J=8.3, 1.8 Hz, 1H), 8.74 (dd, J=5.1, 1.7 Hz, 1H), 9.29(dd, J=2.0, 0.7 Hz, 1H) ppm; MS (DCI/NH₃) m/z 393 (M+H)⁺.

EXAMPLE 71B(R)-3-(Pyridin-3-yl)-5-(3-(pyrrolidin-2-yl)phenyl)-1,2,4-oxadiazolebis(hydrochloric acid)

The title compound was prepared according to the procedure of Example 59using the product of Example 71A. ¹H NMR (300 MHz, DMSO-d₆) δ 1.98-2.27(m, 3H), 2.39-2.50 (m, 1H), 3.22-3.51 (m, 2H), 4.55-4.81 (m, 1H),7.71-7.82 (m, 2H), 7.96 (d, J=7.9 Hz, 1H), 8.26 (dt, J=7.8, 1.2 Hz, 1H),8.40 (s, 1H), 8.58 (dt, J=8.1, 1.9 Hz, 1H), 8.89 (dd, J=5.2, 1.6 Hz,1H), 9.21-9.53 (m, J=1.6 Hz, 2H) ppm; MS (DCI/NH₃) m/z 293 (M+H)⁺.

EXAMPLE 725-(3-(1H-pyrazol-3-yl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to the procedure of Example 8using N′-hydroxynicotinimidamide (Aldrich) and3-(1H-pyrazol-3-yl)benzoic acid (Maybridge). ¹H NMR (300 MHz, DMSO-d₆) δ6.91 (d, J=2.4 Hz, 1H), 7.62-7.69 (m, 1H), 7.72 (t, J=7.8 Hz, 1H),7.79-7.92 (m, 1H), 7.82-7.88 (m, 1H), 8.10-8.20 (m, 3H), 8.49 (dt,J=8.2, 1.9, 1.7 Hz, 1H), 8.64 (s, 1H), 8.83 (dd, J=4.7, 1.7 Hz, 1H),9.29 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 290 (M+H)⁺.

EXAMPLE 73 1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)ethanol

A solution of the product of Example 68 (265 mg, 1.0 mmol) in ethanol (5mL) was stirred with sodium borohydride (Aldrich, 83 mg, 2.2 mmol) atroom temperature for 16 hours. The inorganic solid was filtered off witha syringe filter and the liquid mixture was purified by preparative HPLC(Gilson, column, Xbridge® 5 μm, 30×100 mm. eluting solvent,acetonitrile/water (pH=10, NH₄HCO₃—NH₃.H₂O buffer), v. 5/95 to 95/5 over35 minutes, flow rate, 40 mL/minute, uv, 234 nm). Fractions of thedesired product were collected and concentrated to give the desiredproduct. ¹H NMR (300 MHz, CD₃OD) δ 1.51 (d, J=6.7 Hz, 3H), 4.97 (q,J=6.6 Hz, 1H), 7.57-7.73 (m, 3H), 8.13 (dt, J=7.6, 1.5 Hz, 1H), 8.28 (t,J=1.8 Hz, 1H), 8.57 (dt, J=7.9, 1.8 Hz, 1H), 8.74 (dd, J=5.0, 1.8 Hz,1H), 9.30 (dd, J=2.2, 1.0 Hz, 1H) ppm; MS (DCI/NH₃) m/z 268 (M+H)⁺.

EXAMPLE 74 3-(3-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile

The title compound was prepared according to the procedure of Example 1using the product of Example 53A and 3-cyanobenzoyl chloride (Aldrich).¹H NMR (300 MHz, CDCl₃) δ 7.52 (d, J=7.8 Hz, 1H), 7.75 (t, J=8.0 Hz,1H), 7.93 (d, J=7.8 Hz, 1H), 8.30-8.50 (m, 2H), 8.54 (s, 1H), 9.19 (d,J=2.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z 283 (M+H)⁺, 300 (M+NH₄)⁺.

EXAMPLE 75 3-(4-fluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole

4-Fluoro-N′-hydroxybenzimidamide (0.154 g, 1 mmol) was dissolved inpyridine (10 mL) and nicotinoyl chloride (Aldrich, 0.141 g, 1 mmol) wasadded. The reaction mixture was heated to reflux for 3 hours and thencooled to room temperature. The cooled reaction mixture was quenchedwith water (25 mL) and filtered. The solid was further purified withflash column chromatography (5% methanol/dichloromethane) to give thetitled product. ¹H NMR (300 MHz, DMSO-d₆) δ 7.47 (t, J=6.8 Hz, 2H),7.74-7.70 (m, 1H), 8.20-8.15 (m, 2H), 8.58-8.54 (m, 1H), 8.91-8.89 (dd,J=1.7, 1.7 Hz, 1H), 9.35 (d, J=1.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z 242(M+H)⁺.

EXAMPLE 76 3-(5-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile

The title compound was prepared according to the procedure of Example 4Busing 3-cyano-N′-hydroxybenzimidamide (Example 4A) and6-chloronicotinoyl chloride (Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 7.87(m, 2H), 8.17 (m, 1H), 8.4 (m, 1H), 8.43 (d, J=1.7 Hz, 1H), 8.6 (m, 1H),9.25 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH₃) m/z 283 (M+H)⁺.

EXAMPLE 77 3-(5-(2-fluoropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile

The title compound was prepared according to the procedure of Example 4Busing 3-cyano-N′-hydroxybenzimidamide (Example 4A) and2-fluoronicotinoyl chloride (Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 7.87(m, 1H), 7.95 (m, 1H), 8.17 (m, 1H), 8.17 (m, 1H), 8.43 (m, 1H), 8.6 (m,1H), 8.8 (m, 1H) ppm; MS (DCI/NH₃) m/z 267 (M+H)⁺.

EXAMPLE 783-fluoro-5-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile

The title compound was prepared according to the procedure of Example 4Busing 3-cyano-5-fluoro-N′-hydroxybenzimidamide (Prepared from5-fluoroisophthalonitrile using the procedure described in Example 4A.)and nicotinoyl chloride (Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 7.77 (m,1H), 8.2 (m, 2H), 8.4 (m, 1H), 8.6 (m, 1H), 8.9 (m, 1H), 9.4 (m, 1H)ppm; MS (DCI/NH₃) m/z 267 (M+H)⁺.

EXAMPLE 79 5-(2,3-Difluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazoleEXAMPLE 79A Pyrimidine-5-carboxamide

A solution of ethyl pyrimidine-5-carboxylate (6.10 g, 40.0 mmol) inmethanol (40 mL) was stirred with ammonium hydroxide (4.30 mL, 110 mmol)in a sealed tube at 50° C. for 10 hours. The reaction mixture was thenconcentrated and the residue was stirred in ethanol/ethyl acetate (v/v1/4, 50 mL) at ambient temperature for 2 hours. The white precipitatewas collected by filtration and dried to give the titled compound. ¹HNMR (300 MHz, DMSO-d₆) δ 7.85 [s (broad), 1H], 8.33 [s (broad), 1H],9.18 (s, 2H), 9.32 (s, 1H) ppm; MS (DCI/NH₃) m/z 124 (M+H)⁺, 141(M+NH₄)⁺.

EXAMPLE 79B Pyrimidine-5-carbonitrile

To a suspension of the product of Example 79A (6.75 g, 54.8 mmol) andtriethylamine (Aldrich, 15.28 mL, 110 mmol) in anhydrous CH₂Cl₂(Aldrich, 400 mL) was slowly added a solution of trifluoroaceticanhydride (Aldrich, 9.30 mL, 65.8 mmol) in anhydrous CH₂Cl₂ (100 mL) at0-10° C. over 1 hours. It was then stirred at 0° C. to ambienttemperature for 2 hours. The reaction was then quenched with water (10mL) and washed with NaOH (1 N, 20 mL) and brine (2×10 mL) before beingconcentrated under reduced pressure at less than 30° C. to supply thetitled compound. ¹H NMR (300 MHz, DMSO-d₆) δ 9.34 (s, 2H), 9.47 (s, 1H)ppm; MS (DCI/NH₃) m/z 123 (M+NH₄)⁺.

EXAMPLE 79C N′-Hydroxypyrimidine-5-carboximidamide

A solution of the product of Example 79B (5.47 g, 52 mmol) and aqueoushydroxylamine (Aldrich, 50%, 2.3 mL, 78 mmol) in methanol (50 mL) wasstirred at 65° C. for 1 hour and then concentrated under reducedpressure to remove the volatiles. The residue was triturated with EtOAc(30 mL). The precipitates were collected by filtration and dried to givethe titled compound. ¹H NMR (300 MHz, DMSO-d₆) δ 6.14 (s, 2H), 9.03 (s,2H), 9.18 (s, 1H), 10.06 (s, 1H) ppm; MS (DCI/NH₃) m/z 139 (M+H)⁺, 156(M+NH₄)⁺.

EXAMPLE 79D 5-(2,3-Difluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 79C and 2,3-difluorobenzoyl chloride(Aldrich). ¹H NMR (300 MHz, CDCl₃) δ 7.27-7.39 (m, 1H), 7.42-7.56 (m,1H), 7.95-8.08 (m, 1H), 9.39 (s, 1H), 9.49 (s, 2H) ppm; MS (DCI/NH₃) m/z261 (M+H)⁺.

EXAMPLE 80 5-(pyridin-3-yl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 79C and nicotinoyl chloride hydrochloride(Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 7.74 (ddd, J=8.0, 4.9, 0.7 Hz,1H), 8.54-8.64 (m, 1H), 8.93 (dd, J=4.9, 1.5 Hz, 1H), 9.39 (d, J=1.7 Hz,1H), 9.45 (s, 1H), 9.46 (s, 2H) ppm; MS (DCI/NH₃) m/z 226 (M+H)⁺.

EXAMPLE 812-fluoro-N,N-dimethyl-4-(3-(pyrimidin-5-yl)-1,2,4-oxadiazol-5-yl)aniline

The titled compound was prepared according to the procedure of Method Cusing the product of Example 79C and 3,4-difluorobenzoic acid (Aldrich).¹H NMR (300 MHz, CDCl₃) δ 3.06 (s, 3H), 3.07 (s, 3H), 6.89 (t, J=8.7 Hz,1H), 7.76-7.96 (m, 2H), 9.36 (s, 1H), 9.43-9.47 (m, 2H) ppm; MS(DCI/NH₃) m/z 286 (M+H)⁺.

EXAMPLE 82 3-(3-(pyrimidin-5-yl)-1,2,4-oxadiazol-5-yl)benzonitrile

The titled compound was prepared according to the procedure of Method Dusing the product of Example 79C and 3-cyanobenzoyl chloride (Aldrich).¹H NMR (300 MHz, DMSO-d₆) δ 7.91 (t, J=7.9 Hz, 1H), 8.24 (dt, J=7.7,1.4, 1.2 Hz, 1H), 8.53 (dt, J=8.1, 1.4, 1.2 Hz, 1H), 8.67 (t, J=1.8 Hz,1H), 9.45 (s, 1H), 9.46 (s, 2H) ppm; MS (DCI/NH₃) m/z 250 (M+H)⁺.

EXAMPLE 83 5-(3,4-Difluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazolehydrochloride EXAMPLE 83A Methyl pyridazine-4-carboxylate

To a solution of pyridazine-4-carboxylic acid (Aldrich, 5.0 g, 40.3mmol) in methanol (anhydrous, Aldrich, 100 mL) was added sulfuric acid(concentrated, Aldrich, 2 mL). The reaction mixture was then heated toreflux and stirred for 16 hours. The volatiles were removed underreduced pressure. The residue was basified to pH=8-9 with saturatedsodium carbonate (20 mL) and then extracted with EtOAc (3×100 mL). Thecombined extracts were washed with brine (2×20 mL) and dried overmagnesium sulfate. The drying agent was filtered off and the organicsolution was concentrated and dried to give the titled compound. ¹H NMR(300 MHz, DMSO-d₆) δ 3.34 (s, 3H), 8.10 (dd, J=5.2, 2.4 Hz, 1H), 9.52(dd, J=5.2, 1.2 Hz, 1H), 9.58 (dd, J=2.2, 1.4 Hz, 1H) ppm; MS (DCI/NH₃)m/z 139 (M+H)⁺.

EXAMPLE 83B pyridazine-4-carboxamide

The title compound was prepared according to the procedure of Example79A using the product of Example 83A and ammonium hydroxide (Aldrich).¹H NMR (300 MHz, DMSO-d₆) δ 8.00 (dd, J=5.2, 2.4 Hz, 1H), 8.46 [s(broad), 2H], 9.44 (dd, J=5.2, 1.2 Hz, 1H), 9.55 (dd, J=2.2, 1.4 Hz, 1H)ppm; MS (DCI/NH₃) m/z 124 (M+H)⁺, 141 (M+NH₄)⁺.

EXAMPLE 83C pyridazine-4-carbonitrile

The title compound was prepared according to the procedure of Example79B using the product of Example 83B and trifluoroacetic anhydride(Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 8.28 (dd, J=5.4, 2.2 Hz, 1H),9.57 (dd, J=5.2, 1.2 Hz, 1H), 9.66 (dd, J=2.2, 1.4 Hz, 1H) ppm; MS(DCI/NH₃) m/z 123 (M+NH₄)⁺.

EXAMPLE 83D N′-Hydroxypyridazine-4-carboximidamide

The title compound was prepared according to the procedure of Example79C using the product of Example 83C and hydroxylamine (Aldrich). ¹H NMR(300 MHz, DMSO-d₆) δ 6.19 (s, 2H), 7.87 (dd, J=5.4, 2.4 Hz, 1H), 9.25(dd, J=5.4, 1.4 Hz, 1H), 9.46 (dd, J=2.4, 1.4 Hz, 1H), 10.36 (s, 1H)ppm; MS (DCI/NH₃) m/z 139 (M+H)⁺, 156 (M+NH₄)⁺.

EXAMPLE 83E 5-(3,4-difluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 83D and 3,4-difluorobenzoyl chloride(Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 7.80 (dt, J=10.5, 8.3 Hz, 1H),8.08-8.19 (m, 1H), 8.29 (dd, J=5.4, 2.4 Hz, 1H), 8.31-8.38 (m, 1H), 9.55(dd, J=5.4, 1.4 Hz, 1H), 9.82 (dd, J=2.2, 1.2 Hz, 1H) ppm; MS (DCI/NH₃)m/z 261 (M+H)⁺.

EXAMPLE 83F 5-(3,4-Difluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazolehydrochloride

A solution of the product of Example 83E (140 mg, 0.54 mmol) in ethylacetate (5.0 mL) was stirred with hydrochloric acid (Aldrich, 4 M indioxane, 0.25 mL, 1.0 mmol) at ambient temperature for 10 hours. Thewhite precipitates were collected by filtration and dried to give thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ 7.81 (dt, J=10.5, 8.5 Hz,1H), 8.08-8.19 (m, 1H), 8.26-8.39 (m, 2H), 9.55 (dd, J=5.4, 1.4 Hz, 1H),9.83 (dd, J=2.4, 1.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z 261 (M+H)⁺.

EXAMPLE 84 3-(Pyridazin-4-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 83D and nicotinoyl chloride hydrochloride(Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 7.75 (ddd, J=8.0, 4.9, 0.7 Hz,1H), 8.32 (dd, J=5.3, 2.2 Hz, 1H), 8.61 (dt, J=8.2, 1.8 Hz, 1H), 8.93(dd, J=5.1, 1.7 Hz, 1H), 9.39 (dd, J=2.2, 0.8 Hz, 1H), 9.55 (dd, J=5.4,1.4 Hz, 1H), 9.85 (dd, J=2.2, 1.2 Hz, 1H) ppm; MS (DCI/NH₃) m/z 226(M+H)⁺.

EXAMPLE 85N,N-Dimethyl-N′-(4-(3-(pyrimidin-5-yl)-1,2,4-oxadiazol-5-yl)phenylsulfonyl)formimidamide

The titled compound was prepared according to the procedure of Method Dusing the product of Example 79C and 4-sulfamidobenzoyl chloridedimethylformamide complex (Alfa Aesar). ¹H NMR (300 MHz, DMSO-d₆) δ 2.94(s, 3H), 3.18 (s, 3H), 8.06 (d, J=8.8 Hz, 2H), 8.30 (s, 1H), 8.37 (d,J=8.8 Hz, 2H), 9.45 (s, 1H), 9.46 (s, 2H) ppm; MS (DCI/NH₃) m/z=359(M+H)⁺, 376 (M+NH₄)⁺.

EXAMPLE 86 5-(4-fluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 79C and 4-fluorobenzoyl chloride (Aldrich).¹H NMR (300 MHz, DMSO-d₆) δ 7.51-7.59 (m, 2H), 8.27-8.34 (m, 2H), 9.44(s, 2H), 9.45 (S, 1H) ppm; MS (DCI/NH₃) m/z=243 (M+H)⁺, 260 (M+NH₄)⁺.

EXAMPLE 87 5-(3-fluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 79C and 3-fluorobenzoyl chloride (Aldrich).¹H NMR (300 MHz, DMSO-d₆) δ 7.61-7.71 (m, 1H), 7.72-7.84 (m, 1H), 8.04(ddd, J=9.3, 2.5, 1.4 Hz, 1H), 8.07-8.12 (m, 1H), 9.45 (s, 3H) ppm; MS(DCI/NH₃) m/z=243 (M+H)⁺, 260 (M+NH₄)⁺.

EXAMPLE 88 3-(pyrimidin-5-yl)-5-(3,4,5-trifluorophenyl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 79C and 3,4,5-trifluorobenzoyl chloride(Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 8.24 (dd, J=8.0, 6.6 Hz, 2H),9.44 (s, 2H), 9.46 (s, 1H) ppm; MS (DCI/NH₃) m/z=279 (M+H)⁺, 296(M+NH₄)⁺.

EXAMPLE 89 5-(2-Chloropyridin-4-yl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 79C and 2-chloroisonicotinoyl chloride(Maybridge). ¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (dd, J=5.1, 1.4 Hz, 1H),8.25 (dd, J=1.4, 0.7 Hz, 1H), 8.78 (dd, J=5.1, 0.7 Hz, 1H), 9.46 (s,1H), 9.47 (s, 2H) ppm; MS (DCI/NH₃) m/z=260 (M+H)⁺, 262 (M+H)⁺.

EXAMPLE 90 3-(Pyridin-3-yl)-5-(pyrimidin-5-yl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Cusing N′-hydroxynicotinimidamide (Tyger) and pyrimidine-5-carboxylicacid (Maybridge). ¹H NMR (300 MHz, DMSO-d₆) δ 7.68 (ddd, J=8.0, 4.9, 1.0Hz, 1H), 8.48 (dt, J=7.7, 2.1 Hz, 1H), 8.84 (dd, J=4.7, 1.7 Hz, 1H),9.29 (dd, J=2.4, 1.0 Hz, 1H), 9.51 (s, 1H), 9.56 (s, 2H) ppm; MS(DCI/NH₃) m/z=226 (M+H)⁺, 243 (M+NH₄)⁺.

EXAMPLE 91 5-(Pyridazin-4-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Cusing N′-hydroxynicotinimidamide (Aldrich) and pyridazine-4-carboxylicacid (Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.67 (ddd, J=8.1, 5.0, 0.8 Hz,1H), 8.45 (dd, J=5.4, 2.4 Hz, 1H), 8.60 (dt, J=8.1, 1.9 Hz, 1H), 8.78(dd, J=5.1, 1.7 Hz, 1H), 9.34 (dd, J=2.2, 0.8 Hz, 1H), 9.55 (dd, J=5.4,1.4 Hz, 1H), 9.94 (dd, J=2.2, 1.2 Hz, 1H) ppm; MS (DCI/NH₃) m/z=226(M+H)⁺.

EXAMPLE 92 3-(3-(Pyridazin-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile

The titled compound was prepared according to the procedure of Method Dusing the product of Example 83D and 3-cyanobenzoyl chloride (Aldrich).¹H NMR (300 MHz, CD₃OD) δ 7.86 (t, J=7.9 Hz, 1H), 8.09 (ddd, J=8.1, 1.4,1.2 Hz, 1H), 8.40 (dd, J=5.4, 2.2 Hz, 1H), 8.55 (dt, J=7.9, 1.6 Hz, 1H),8.64 (t, J=2.0 Hz, 1H), 9.46 (dd, J=5.4, 1.4 Hz, 1H), 9.88 (dd, J=2.2,1.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z=250 (M+H)⁺.

EXAMPLE 93 5-(3-Fluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 83D and 3-fluorobenzoyl chloride (Aldrich).¹H NMR (300 MHz, CD₃OD) δ 7.45-7.53 (m, 1H), 7.69 (td, J=8.1, 5.6 Hz,1H), 8.00 (ddd, J=9.1, 2.6, 1.4 Hz, 1H), 8.11 (dt, J=7.9, 1.2 Hz, 1H),8.39 (dd, J=5.4, 2.2 Hz, 1H), 9.45 (dd, J=5.2, 1.2 Hz, 1H), 9.87 (dd,J=2.2, 1.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z=243 (M+H)⁺.

EXAMPLE 94 3-(Pyridazin-4-yl)-5-(3,4,5-trifluorophenyl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 83D and 3,4,5-trifluorobenzoyl chloride(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 8.04-8.16 (m, 2H), 8.38 (dd, J=5.4,2.2 Hz, 1H), 9.46 (dd, J=5.4, 1.4 Hz, 1H), 9.86 (dd, J=2.4, 1.2 Hz, 1H)ppm; MS (DCI/NH₃) m/z=279 (M+H)⁺.

EXAMPLE 95 5-(3,5-difluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 83D and 3,5-difluorobenzoyl chloride(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.40 (tt, J=8.9, 2.4 Hz, 1H),7.85-7.94 (m, 2H), 8.39 (dd, J=5.4, 2.2 Hz, 1H), 9.46 (dd, J=5.4, 1.4Hz, 1H), 9.87 (dd, J=2.2, 1.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z=261 (M+H)⁺.

EXAMPLE 96 5-(4-fluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 83D and 4-fluorobenzoyl chloride (Aldrich).¹H NMR (300 MHz, CD₃OD) δ 7.36-7.45 (m, 2H), 8.29-8.40 (m, 3H), 9.45(dd, J=5.6, 1.2 Hz, 1H), 9.86 (dd, J=2.4, 1.2 Hz, 1H) ppm; MS (DCI/NH₃)m/z=243 (M+H)⁺.

EXAMPLE 97 3-(pyridazin-4-yl)-5-(pyrimidin-5-yl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Cusing the product of Example 83D and pyrimidine-5-carboxylic acid(Maybridge). ¹H NMR (300 MHz, CD₃OD) δ 8.41 (dd, J=5.4, 2.4 Hz, 1H),9.44 (s, 1H), 9.47 (dd, J=5.4, 1.4 Hz, 1H), 9.59 (s, 2H), 9.90 (dd,J=2.2, 1.2 Hz, 1H) ppm; MS (DCI/NH₃) m/z=227 (M+H)⁺.

EXAMPLE 98 3-(pyridazin-4-yl)-5-(2,36-trifluorophenyl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 83D and 2,3,6-trifluorobenzoyl chloride(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.28-7.37 (m, J=9.5, 9.5, 3.7, 2.4Hz, 1H), 7.67-7.79 (m, J=9.6, 9.6, 8.7, 4.9 Hz, 1H), 8.39 (dd, J=5.3,2.2 Hz, 1H), 9.46 (dd, J=5.3, 1.2 Hz, 1H), 9.88 (dd, J=2.2, 1.2 Hz, 1H)ppm; MS (DCI/NH₃) m/z=279 (M+H)⁺.

EXAMPLE 99 3-(pyridazin-4-yl)-5-(2,3,4-trifluorophenyl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 83D and 2,3,4-trifluorobenzoyl chloride(Aldrich). ¹H NMR (300 MHz, CD₃OD) δ 7.40-7.50 (m, J=9.3, 9.3, 7.0, 2.2Hz, 1H), 8.10-8.20 (m, 1H), 8.39 (dd, J=5.4, 2.4 Hz, 1H), 9.46 (dd,J=5.3, 1.2 Hz, 1H), 9.87 (dd, J=2.2, 1.2 Hz, 1H) ppm; MS (DCI/NH₃)m/z=279 (M+H)⁺.

EXAMPLE 100N,N-dimethyl-N′-(4-(3-(pyridazin-4-yl)-1,2,4-oxadiazol-5-yl)phenylsulfonyl)formimidamide

The titled compound was prepared according to the procedure of Method Dusing the product of Example 83D and 4-sulfamidobenzoyl chloridedimethylformamide complex (Alfa Aesar). ¹H NMR (300 MHz, CD₃OD) δ 2.95(s, 3H), 3.18 (s, 3H), 8.06 (d, J=8.5 Hz, 2H), 8.29 (s, 1H), 8.31 (dd,J=5.3, 2.2 Hz, 1H), 8.37 (d, J=8.8 Hz, 2H), 9.54 (dd, J=5.1, 1.4 Hz,1H), 9.83 (dd, J=2.4, 1.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z=359 (M+H)⁺.

EXAMPLE 101 5-(3,4-difluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazoletosylate EXAMPLE 101A5-(3,4-Difluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 79C and 3,4-difluorobenzoyl chloride(Aldrich). ¹H NMR (300 MHz, CDCl₃) δ 7.35-7.48 (m, 1H), 7.97-8.13 (m,2H), 9.40 (s, 1H), 9.49 (s, 2H) ppm; MS (DCI/NH₃) m/z 261 (M+H)⁺.

EXAMPLE 101B 5-(3,4-Difluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazoletosylate

A solution of the product of Example 101A (52 mg, 0.2 mmol) in ethylacetate (5 mL) was stirred with a solution of p-toluenesulfonic acidmonohydrate (Aldrich, 46.0 mg, 0.24 mmol) in ethyl acetate (1.0 mL) atambient temperature for 10 hours. The precipitates were collected byfiltration and dried to give the title compound. ¹H NMR (300 MHz, CDCl₃)δ 2.40 (s, 3H), 7.25 (d, J=8.2 Hz, 2H), 7.36-7.53 (m, 1H), 7.83 (d,J=8.3 Hz, 2H), 8.03-8.12 (m, 2H), 9.57 (s, 1H), 9.71 (s, 2H); MS(DCI/NH₃) m/z 261 (M+H)⁺.

EXAMPLE 102 3-(3,4-difluorophenyl)-5-(pyrimidin-5-yl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing 3,4-difluoro-N′-hydroxybenzimidamide (Tyger) andpyrimidine-5-carbonyl chloride. The pyrimidine-5-carbonyl chloride wasprepared by the reaction of pyrimidine-5-carboxylic acid (Maybridge, 138mg, 1.0 mmol) with oxalyl chloride (Aldrich, 2 M, in CH₂Cl₂, 1.0 mL, 2.0mmol) and a drop of dimethylformamide at room temperature over 1 hourwith subsequent removal of volatiles under reduced pressure. ¹H NMR (300MHz, DMSO-d₆) δ 7.72 (dt, J=10.5, 8.5 Hz, 1H), 7.94-8.05 (m, 1H), 8.11(ddd, J=10.9, 7.7, 2.0 Hz, 1H), 8.12 (none, 1H), 9.51 (s, 1H), 9.54 (s,2H) ppm; MS (DCI/NH₃) m/z 261 (M+H)⁺.

EXAMPLE 1033-(Pyrimidin-5-yl)-5-(2,3,4-trifluorophenyl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 79C and 2,3,4-trifluorobenzoyl chloride(Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 7.58-7.75 (m, 1H), 8.03-8.26 (m,1H), 9.44 (s, 2H), 9.45 (s, 1H) ppm; MS (DCI/NH₃) m/z 279 (M+H)⁺, 296(M+NH₄)⁺.

EXAMPLE 104 3-(pyrimidin-5-yl)-5-(2,36-trifluorophenyl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 79C and 2,3,6-trifluorobenzoyl chloride(Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 7.48-7.61 (m, 1H), 7.89-8.07 (m,1H), 9.44 (s, 2H), 9.45 (s, 1H) ppm; MS (DCI/NH₃) m/z 279 (M+H)⁺, 296(M+NH₄)⁺.

EXAMPLE 1053-(pyrimidin-5-yl)-5-(2,3,4,5-tetrafluorophenyl)-1,2,4-oxadiazole

The titled compound was prepared according to the procedure of Method Dusing the product of Example 79C and 2,3,4,5-tetrafluorobenzoyl chloride(Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 8.18-8.42 (m, 1H), 9.45 (s, 2H),9.46 (s, 1H) ppm; MS (DCI/NH₃) m/z 297 (M+H)⁺, 314 (M+NH₄)⁺.

EXAMPLE 1065-(imidazo[1,5-a]pyridin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method C usingimidazo[1,2-a]pyridine-6-carboxylic acid (Maybridge) andN′-hydroxynicotinimidamide (Tyger). ¹H NMR (300 MHz, DMSO-d₆) δ 7.67(ddd, J=8.1, 4.8, 1.0 Hz, 1H), 7.76 (d, J=1.4 Hz, 1H), 7.78-7.92 (m,2H), 8.21 (s, 1H), 8.46 (dt, J=8.2, 1.8 Hz, 1H), 8.83 (dd, J=4.7, 1.7Hz, 1H), 9.27 (dd, J=2.2, 0.8 Hz, 1H), 9.69 (dd, J=1.7, 1.0 Hz, 1H) ppm;MS (DCI/NH₃) m/z 264 (M+H)⁺.

EXAMPLE 107 5-(1H-indol-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method C using1H-indole-6-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide(Tyger). ¹H NMR (300 MHz, DMSO-d₆) δ 6.62 (ddd, J=3.0, 1.9, 0.8 Hz, 1H),7.62-7.71 (m, 2H), 7.76-7.89 (m, 2H), 8.27-8.33 (m, J=1.4 Hz, 1H), 8.46(dt, J=8.2, 1.9, 1.7 Hz, 1H), 8.82 (dd, J=4.7, 1.7 Hz, 1H), 9.27 (dd,J=2.2, 0.8 Hz, 1H), 11.66 (s, 1H) ppm; MS (DCI/NH₃) m/z 263 (M+H)⁺.

EXAMPLE 1085-(2,7-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according Method C using2,7-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (Maybridge) andN′-hydroxynicotinimidamide (Tyger). ¹H NMR (300 MHz, DMSO-d₆) δ2.52 (s,3H), 3.27 (s, 3H), 6.77 (s, 1H), 7.67 (ddd, J=8.0, 4.9, 0.7 Hz, 1H),8.48 (dt, J=8.6, 1.9 Hz, 1H), 8.84 (dd, J=4.7, 1.7 Hz, 1H), 9.06 (s,1H), 9.30 (dd, J=2.2, 0.8 Hz, 1H), 9.30 (d, J=1.4 Hz, 1H) ppm; MS(DCI/NH₃) m/z 293 (M+H)⁺.

EXAMPLE 1095-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method C using2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid (Aldrich) andN′-hydroxynicotinimidamide (Tyger). ¹H NMR (300 MHz, DMSO-d₆) δ 7.66(ddd, J=8.1, 4.8, 1.0 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 8.14 (dd, J=8.5,1.7 Hz, 1H), 8.25 (d, J=1.7 Hz, 1H), 8.44 (dt, J=8.2, 1.9, 1.7 Hz, 1H),8.82 (dd, J=4.7, 1.7 Hz, 1H), 9.25 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS(DCI/NH₃) m/z 304 (M+H)⁺.

EXAMPLE 1105-(2-methylbenzofuran-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method C using2-methylbenzofuran-5-carboxylic acid (Chembridge) andN′-hydroxynicotinimidamide (Tyger). ¹H NMR (300 MHz, DMSO-d₆) δ 3.33 (s,3H), 6.58-6.97 (m, 1H), 7.66 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.78 (d,J=8.5 Hz, 1H), 8.40-8.55 (m, 2H), 8.82 (dd, J=4.7, 1.7 Hz, 1H), 9.27(dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 278 (M+H)⁺.

EXAMPLE 1115-(benzo[d][1,2,3]thiadiazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method C usingbenzo[d][1,2,3]thiadiazole-5-carboxylic acid (Maybridge) andN′-hydroxynicotinimidamide (Tyger). ¹H NMR (300 MHz, DMSO-d₆) δ 7.69(ddd, J=8.0, 4.9, 0.7 Hz, 1H), 8.51 (dt, J=8.2, 1.9, 1.7 Hz, 1H), 8.57(dd, J=8.5, 1.7 Hz, 1H), 8.73 (d, J=7.8 Hz, 1H), 8.85 (dd, J=4.9, 1.5Hz, 1H), 9.32 (dd, J=2.4, 1.0 Hz, 1H), 9.51 (dd, J=1.7, 0.7 Hz, 1H) ppm;MS (DCI/NH₃) m/z 282 (M+H)⁺.

EXAMPLE 1125-(1H-benzo[d]imidazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method C using1H-benzo[d]imidazole-5-carboxylic acid (Aldrich) andN′-hydroxynicotinimidamide (Tyger). ¹H NMR (300 MHz, DMSO-d₆) δ 7.66(ddd, J=8.1, 4.8, 1.0 Hz, 1H), 7.75-7.98 (m, 1H), 7.99-8.17 (m, 1H),8.34-8.56 (m, 3H), 8.82 (dd, J=5.1, 1.7 Hz, 1H), 9.28 (dd, J=2.2, 0.8Hz, 1H) ppm; MS (DCI/NH₃) m/z 264 (M+H)⁺.

EXAMPLE 1135-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method C using1H-benzo[d][1,2,3]triazole-5-carboxylic acid (Aldrich) andN′-hydroxynicotinimidamide (Tyger). ¹H NMR (300 MHz, DMSO-d₆) δ 7.67(ddd, J=8.0, 4.9, 0.7 Hz, 1H), 8.10-8.20 (m, 1H), 8.22-8.31 (m, 1H),8.49 (dt, J=8.1, 2.0, 1.7 Hz, 1H), 8.75-8.92 (m, 2H), 9.30 (dd, J=2.2,0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 265 (M+H)⁺.

EXAMPLE 114 5-(benzo[d]thiazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method C usingbenzo[d]thiazole-5-carboxylic acid (Apollo) andN′-hydroxynicotinimidamide (Tyger). ¹H NMR (300 MHz, DMSO-d₆) δ7.64-7.73 (m, 1H), 8.35 (s, 1H), 8.36 (s, 1H), 8.48 (dt, J=8.1, 2.0, 1.7Hz, 1H), 8.83 (dd, J=4.7, 1.7 Hz, 1H), 9.17 (t, J=1.2 Hz, 1H), 9.29 (dd,J=2.2, 0.8 Hz, 1H), 9.66 (s, 1H) ppm; MS (DCI/NH₃) m/z 281 (M+H)⁺.

EXAMPLE 1153-(pyridin-3-yl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method C using1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (Adesis) andN′-hydroxynicotinimidamide (Tyger). ¹H NMR (300 MHz, DMSO-d₆) δ 6.71 (d,J=3.4 Hz, 1H), 7.66 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.70 (d, J=3.4 Hz,1H), 8.47 (dt, J=8.1, 1.9 Hz, 1H), 8.78-8.86 (m, 2H), 9.05 (d, J=2.0 Hz,1H), 9.28 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 264 (M+H)⁺.

EXAMPLE 116 5-(1H-indol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method C using1H-indole-5-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide(Tyger). ¹H NMR (300 MHz, DMSO-d₆) δ 6.69 (dt, J=2.3, 1.4 Hz, 1H), 7.55(t, J=2.7 Hz, 1H), 7.62-7.70 (m, 2H), 7.94 (dd, J=8.8, 1.7 Hz, 1H), 8.46(dt, J=8.1, 1.9 Hz, 1H), 8.49-8.52 (m, 1H), 8.81 (dd, J=4.7, 1.7 Hz,1H), 9.27 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 263 (M+H)⁺.

EXAMPLE 117 5-(benzofuran-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method C usingbenzofuran-5-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide(Tyger). ¹H NMR (300 MHz, DMSO-d₆) δ 7.20 (dd, J=2.0, 1.0 Hz, 1H), 7.66(ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.91 (dt, J=8.6, 1.0, 0.8 Hz, 1H),8.14-8.24 (m, 2H), 8.47 (dt, J=7.9, 2.0 Hz, 1H), 8.60 (d, J=1.4 Hz, 1H),8.82 (dd, J=4.7, 1.7 Hz, 1H), 9.28 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS(DCI/NH₃) m/z 264 (M+H)⁺.

EXAMPLE 1185-(1-methyl-1H-benzo[d]imidazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method C using1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (Maybridge) andN′-hydroxynicotinimidamide (Tyger). ¹H NMR (300 MHz, DMSO-d₆) δ7.65(ddd, J=8.0, 4.9, 0.7 Hz, 1H), 7.68-7.88 (m, J=8.8 Hz, 1H), 7.87-8.10(m, 2H), 8.14-8.37 (m, 1H), 8.46 (dt, J=8.1, 1.9 Hz, 1H), 8.82 (dd,J=4.7, 1.7 Hz, 1H), 9.27 (dd, J=2.0, 0.7 Hz, 1H) ppm; MS (DCI/NH₃) m/z278 (M+H)⁺.

EXAMPLE 1193-(imidazo[1,2-a]pyridin-6-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method D usingN′-hydroxyimidazo[1,2-a]pyridine-6-carboximidamide (Bionet) andnicotinoyl chloride, hydrochloric Acid (Aldrich). ¹H NMR (300 MHz,DMSO-d₆) δ 7.62-7.91 (m, 4H), 8.20 (s, 1H), 8.56 (dt, J=8.1, 1.9 Hz,1H), 8.92 (dd, J=4.7, 1.7 Hz, 1H) ppm; MS (DCI/NH₃) m/z 264 (M+H)⁺.

EXAMPLE 1205-(6-chloropyridin-3-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method D usingN′-hydroxyimidazo[1,2-a]pyridine-6-carboximidamide (Bionet) and6-chloronicotinoyl chloride (Aldrich). ¹H NMR (300 MHz, DMSO-d₆) δ 7.70(d, J=1.2 Hz, 1H), 7.74-7.84 (m, 2H), 7.87 (d, J=8.3 Hz, 1H), 8.20 (s,1H), 8.59 (dd, J=8.5, 2.6 Hz, 1H), 9.20 (dd, J=2.4, 0.8 Hz, 1H), 9.47(t, J=1.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z 298 (M+H)⁺, 300 (M+H)⁺.

EXAMPLE 1215-(6-fluoropyridin-3-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method C usingN′-hydroxyimidazo[1,2-a]pyridine-6-carboximidamide (Bionet) and6-fluoronicotinic acid (Frontier). ¹H NMR (300 MHz, DMSO-d₆) δ 7.55(ddd, J=8.5, 2.7, 0.7 Hz, 1H), 7.70 (d, J=1.4 Hz, 1H), 7.73-7.86 (m,2H), 8.20 (s, 1H), 8.75 (ddd, J=8.1, 2.5 Hz, 1H), 9.08 (dt, J=1.7, 0.8Hz, 1H), 9.46 (dd, J=1.7, 1.0 Hz, 1H) ppm; MS (DCI/NH₃) m/z 282 (M+H)⁺.

EXAMPLE 1225-(5-fluoropyridin-3-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-1,2,4-oxadiazole

The title compound was prepared according to method C usingN′-hydroxyimidazo[1,2-a]pyridine-6-carboximidamide (Bionet) and5-fluoronicotinic acid (Frontier). ¹H NMR (300 MHz, DMSO-d₆) δ 7.71 (d,J=1.4 Hz, 1H), 7.74-7.88 (m, 2H), 8.20 (s, 1H), 8.51 (ddd, J=9.0, 2.9,1.7 Hz, 1H), 8.97 (d, J=3.1 Hz, 1H), 9.24 (t, J=1.5 Hz, 1H), 9.47 (t,J=1.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z 282 (M+H)⁺.

EXAMPLE 123 5-(1H-indazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method C using1H-indazole-5-carboxylic acid (ABCR) and N′-hydroxynicotinimidamide(Tyger). ¹H NMR (300 MHz, DMSO-d₆) δ 7.7 (dd, J=7.9, 4.8 Hz, 1H), 7.8(d, J=8.7 Hz, 1H), 8.2 (dd, J=8.7, 1.6 Hz, 1H), 8.4 (s, 1H) 8.5 (dt,J=7.9, 1.8 Hz, 1H), 8.7 (s, 1H) 8.8 (dd, J=4.8, 1.6 Hz, 1H), 9.3 (d,J=2.0 Hz, 1H), 13.6 (s, 1H) ppm; MS (DCI/NH₃) m/z 264 (M+H)⁺.

EXAMPLE 1245-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazoleEXAMPLE 124A 5-(6-Chloropyridin-3-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to Method D usingN′-hydroxynicotinimidamide (Tyger) and 6-chloronicotinoyl chloride(Aldrich). ¹H NMR (300 MHz, CDCl₃) δ 7.48 (dd, J=7.6, 5.3 Hz, 1H), 7.57(d, J=8.5 Hz, 1H), 8.40-8.48 (m, 2H), 8.80 (dd, J=4.7, 1.7 Hz, 1H), 9.24(d, J=2.4 Hz, 1H), 9.40 (d, J=2.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z 259(M+H)⁺, 261 (M+H)⁺.

EXAMPLE 124B5-(6-Hydrazinylpyridin-3-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

A suspension of the product of Example 126A (260 mg, 1 mmol) in EtOH (15mL) was stirred with hydrazine (Aldrich, 50 mg, 2.5 mmol) at refluxingtemperature for 2 h and then cooled to room temperature. Theprecipitates were collected by filtration, washed with addition cooledEtOH (5 mL) and dried to gave the title compound. ¹NMR (DMSO-d₆): δ6.77-7.08 (m, 1H), 7.35-7.44 (m, 2H), 7.63 (ddd, J=8.0, 4.9, 1.0 Hz,1H), 7.79 (tt, J=7.6, 1.9 Hz, 1H), 8.12 (dd, J=8.8, 2.4 Hz, 1H), 8.41(dt, J=8.1, 1.9 Hz, 1H), 8.58 (dt, J=4.0, 1.9 Hz, 1H), 8.75-8.84 (m,1H), 9.22 (dd, J=2.2, 0.8 Hz, 1H) ppm, MS (DCI/NH₃) m/z=255 (M+H)⁺.

EXAMPLE 124C5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

A suspension of the product of Example 126B (80 mg, 0.31 mmol) intriethoxymethane (Aldrich, 4 mL) was heated to reflux for 16 hours. Thereaction mixture was cooled to room temperature and the volatiles wereremoved under vacuum. The residue was purified with chromatography(SiO₂, EtOAc/CH₂Cl₂=1/9) to give the title compound. ¹H NMR (DMSO-d₆): δ7.68 (dd, J=8.1, 5.0 Hz, 1H), 7.90-8.11 (m, 2H), 8.46 (dt, J=7.9, 2.0Hz, 1H), 8.84 (dd, J=4.8, 1.6 Hz, 1H), 9.27 (d, J=2.0 Hz, 1H), 9.44 (s,1H), 9.68 (s, 1H) ppm; MS (DCI/NH₃) m/z=265 (M+H)⁺.

EXAMPLE 1255-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2(3H)-one

The title compound was prepared according to Method C using2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxylic acid (Matrix) andN′-hydroxynicotinimidamide (Tyger). ¹H NMR (300 MHz, CD₃OD) δ 7.40 (d,J=8.5 Hz, 1H), 7.64 (ddd, J=8.0, 5.0, 0.9 Hz, 1H), 7.90 (d, J=1.7 Hz,1H), 8.01 (dd, J=8.3, 1.9 Hz, 1H), 8.55 (dt, J=7.8, 1.9 Hz, 1H), 8.74(dd, J=4.8, 1.7 Hz, 1H), 9.29 (dd, J=2.2, 0.9 Hz, 1H). ppm; MS (DCI/NH₃)m/z 281 (M+H)⁺.

EXAMPLE 1265-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazole-2(3H)-thione

The title compound was prepared according to Method C using2-mercapto-5-benzimidazolecarboxylic acid (Princeton) andN′-hydroxynicotinimidamide (Tyger). ¹H NMR (300 MHz, CD₃OD) δ 7.38 (d,J=8.5 Hz, 1H), 7.65 (ddd, J=8.0, 4.9, 0.7 Hz, 1H), 7.86 (d, J=1.0 Hz,1H), 8.00 (dd, J=8.1, 1.7 Hz, 1H), 8.45 (dt, J=8.0, 1.9 Hz, 1H), 8.81(dd, J=4.9, 1.5 Hz, 1H), 9.26 (dd, J=2.2, 0.9 Hz, 1H) ppm; MS (DCI/NH₃)m/z 296 (M+H)⁺.

EXAMPLE 1271,3-dimethyl-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one

The title compound was prepared according to Method C using1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid(Matrix) and N′-hydroxynicotinimidamide (Tyger). ¹H NMR (300 MHz, CD₃OD)δ 3.49 (s, 3H), 3.53 (s, 3H), 7.36 (d, J=8.3 Hz, 1H), 7.64 (ddd, J=8.0,5.1, 0.8 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 8.08 (dd, J=8.3, 1.6 Hz, 1H),8.55 (dt, J=8.0, 1.9 Hz, 1H), 8.73 (dd, J=4.8, 1.6 Hz, 1H) 9.29 (d,J=1.2 Hz, 1H). MS (DCI/NH₃) m/z 308 (M+H)⁺.

EXAMPLE 1286-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2(3H)-one

The title compound was prepared according to Method C using2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid (Eur. J. Med. Chem.1974, 9, 491-6.) and N′-hydroxynicotinimidamide (Tyger). ¹H NMR (300MHz, DMSO-d₆) δ 7.35 (d, J=8.7 Hz, 1H), 7.65 (dd, J=7.5, 4.4 Hz, 1H),8.04 (d, J=1.6 Hz, 1H), 8.07 (s, 1H), 8.44 (dt, J=7.9, 2.0 Hz, 1H), 8.82(dd, J=4.8, 1.6 Hz, 1H), 9.25 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH₃) m/z281 (M+H)⁺.

EXAMPLE 1295-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazol-2(3H)-onetrifluoroacetic Acid

A solution of 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid(Princeton, 178 mg, 1.0 mmol) in CH₂Cl₂ (anhydrous, 5.0 mL) was stirredwith oxalyl chloride (Aldrich, 2 M, in CH₂Cl₂, 1.0 mL) in the presenceof 2 drops dimethylformamide at room temperature for 1 hour. It was thenconcentrated and dried under reduced pressure. The residue was dissolvedin pyridine (5.00 mL) and then stirred with N′-hydroxynicotinimidamide(Tyger, 137 mg, 1.0 mmol) at 100° C. for 16 hours. The reaction mixturewas cooled to ambient temperature, diluted with EtOAc (50 mL), washedwith water (2×10 mL) and brine. The organic solution was concentratedunder reduced pressure, purified with preparative HPLC [Waters, column:Xbridge™ Prep C18 5 μm, OBD 30×100 mm, solvent: acetonitrile/water (v.1% TFA), 5/95 to 95/5, flow rate of 40 mL/minute. Fractions werecollected based upon UV signal threshold.] the title compound. ¹H NMR(300 MHz, CD₃OD) δ 7.25 (d, J=8.3 Hz, 1H), 7.75 (ddd, J=7.9, 5.2, 0.8Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.99 (dd, J=8.3, 1.6 Hz, 1H), 8.68 (dt,J=7.9, 1.8 Hz, 1H), 8.79 (dd, J=5.2, 1.6 Hz, 1H), 9.33 (d, J=1.2 Hz, 1H)ppm. MS (DCI/NH₃) m/z 280 (M+H)⁺.

EXAMPLE 1306-(3-(Pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2-amine EXAMPLE130A 2-nitro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol

The title compound was prepared according to Method C using3-hydroxy-4-nitrobenzoic acid (Aldrich) and N′-hydroxynicotinimidamide(Tyger). ¹H NMR (300 MHz, DMSO-d₆) δ 7.67 (ddd, J=7.9, 4.8, 0.8 Hz, 1H),7.76 (dd, J=8.5, 1.8 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 8.12 (d, J=8.3 Hz,1H), 8.45 (dt, J=7.9, 2.0 Hz, 1H), 8.83 (dd, J=4.8, 1.6 Hz, 1H), 9.26(d, J=1.2 Hz, 1H)) ppm; MS (DCI/NH₃) m/z 285 (M+H)⁺.

EXAMPLE 130B 2-amino-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol

A solution of the product of Example 132A (1.0 g, 3.52 mmol) in THF(20.0 mL) was stirred with Raney nickel (Aldrich, 4.0 g) under H₂ (30psi) for 2 hours. The catalyst was then carefully removed by filtrationand the reaction mixture was concentrated to give the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ 5.67 (s, 2H), 6.74 (d, J=8.1 Hz, 1H), 7.40-7.52(m, 2H), 7.62 (dd, J=8.0, 4.2 Hz, 1H), 8.39 (dt, J=8.0, 2.0, 1.9 Hz,1H), 8.78 (dd, J=4.7, 1.7 Hz, 1H), 9.20 (d, J=1.7 Hz, 1H), 9.65-9.98 (m,J=3.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z 255 (M+H)⁺.

EXAMPLE 130C6-(3-(Pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2-amine

To a solution of the product of Example 132B (254 mg, 1.0 mmol) in THF(20 ml) was added cyanic bromide (Aldrich, 106 mg, 1.0 mmol) andtriethylamine (Aldrich, 0.14 ml, 1.0 mmol). The mixture was then stirredat 50° C. for 10 h, cooled to ambient temperature, triturated with water(40 mL). The precipitate was filtered and dried under vacuum to give thetitled compound. ¹H NMR (300 MHz, DMSO-d₆) δ 7.42 (d, J=8.1 Hz, 1H),7.65 (dd, J=7.8, 5.1 Hz, 1H), 7.98 (s, 2H), 8.02 (dd, J=8.1, 1.7 Hz,1H), 8.12 (d, J=1.7 Hz, 1H), 8.44 (dt, J=8.1, 1.9 Hz, 1H), 8.81 (dd,J=4.7, 1.7 Hz, 1H), 9.26 (d, J=1.4 Hz, 1H) ppm; MS (DCI/NH₃) m/z 280(M+H)⁺.

EXAMPLE 131 6-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazole

To a solution of the product of Example 132B (508 mg, 2.0 mmol) intriethyl orthoformate (Aldrich, 20 mL, 120 mmol) was stirred at 100° C.for 10 hours. It was then cooled to ambient temperature, and thentriturated with hexanes (50 mL). The precipitate was filtered and driedunder vacuum to give the titled compound. ¹H NMR (300 MHz, DMSO-d₆) δ7.67 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 8.28 (dd,J=8.3, 1.6 Hz, 1H), 8.48 (dt, J=7.9, 2.0 Hz, 1H), 8.66 (d, J=1.6 Hz,1H), 8.83 (dd, J=4.8, 1.6 Hz, 1H), 9.04 (s, 1H), 9.29 (d, J=2.4 Hz, 1H)ppm; MS (DCI/NH₃) m/z 265 (M+H)⁺.

EXAMPLE 1325-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzo[d]oxazol-2(3H)-oneEXAMPLE 132A 2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbonitrile

A solution of 3-Amino-4-hydroxybenzonitrile (Betapharma, 537 mg, 4 mmol)in CH₂Cl₂ (20 ml) was stirred with N,N′-carbonyldiimidazole (Aldrich,713 mg, 4.40 mmol) at room temperature for 16 hours. It was thenconcentrated under reduced pressure. The residue was stirred with water(10 mL) for 5 minutes, and extracted with EtOAc (3×10 mL). The combinedextracts were concentrated to the title compound. ¹H NMR (300 MHz,CD₃OD) δ 7.17-7.22 (m, 1H), 7.28-7.34 (m, 2H) ppm; MS (DCI/NH₃) m/z 178(M+NH₄)⁺.

EXAMPLE 132BN′-Hydroxy-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboximidamide

A solution of the product from Example 134A (300 mg, 1.9 mmol),hydroxylammonium chloride (Aldrich, 64.0 mg, 1.9 mmol) and triethylamine(Aldrich, 227 mg, 2.3 mmol), in methanol (10 mL) was stirred at 65° C.for 2 h, cooled to ambient temperature, then concentrated under reducedpressure. The residue was triturated with EtOAc (10 mL). The precipitatewas filtered and dried under vacuum to give the titled compound. ¹H NMR(300 MHz, CD₃OD) δ 7.22 (d, J=8.33 Hz, 1H) 7.34-7.43 (m, 2H). MS(DCI/NH₃) m/z 194 (M+H)⁺.

EXAMPLE 132C5-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzo[d]oxazol-2(3H)-one

The title compound was prepared according to Method D using the productof Example 134B and nicotinoyl chloride (Aldrich). ¹H NMR (300 MHz,CD₃OD) δ 7.51 (d, J=8.7 Hz, 1H), 7.68-7.75 (m, 2H), 7.87 (dd, J=8.3, 2.0Hz, 1H), 8.57 (dt, J=7.9, 2.0 Hz, 1H), 8.90 (dd, J=5.0, 1.8 Hz, 1H),9.36 (d, J=1.6 Hz, 1H) ppm. MS (DCI/NH₃) m/z 281 (M+H)⁺.

EXAMPLE 1335-(5-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzo[d]oxazol-2(3H)-one

The title compound was prepared according to Method D using the productof Example 134B and 6-chloronicotinoyl chloride (Aldrich). ¹H NMR (300MHz, CD₃OD) δ 7.33 (d, J=8.3 Hz, 1H), 7.73 (dd, J=8.3, 0.8 Hz, 1H), 7.82(d, J=1.6 Hz, 1H), 7.91 (dd, J=8.3, 1.6 Hz, 1H), 8.57 (dd, J=8.3, 2.4Hz, 1H), 9.19 (d, J=2.4 Hz, 1H) ppm. MS (DCI/NH₃) m/z 315 317 (M+H)⁺.

EXAMPLE 1345-(benzo[d][1,3]dioxol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole

The title compound was prepared according to method C usingbenzo[d][1,3]dioxole-5-carboxylic acid (Aldrich) andN′-hydroxynicotinimidamide (Tyger). ¹H NMR (300 MHz, DMSO-d₆) δ 6.22 (s,2H), 7.20 (d, J=8.1 Hz, 1H), 7.61-7.69 (m, 2H), 7.81 (dd, J=8.1, 1.7 Hz,1H), 8.42 (dt, J=8.2, 1.9, 1.7 Hz, 1H), 8.81 (dd, J=4.7, 1.7 Hz, 1H),9.24 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH₃) m/z 268 (M+H)⁺.

In addition to the specific compounds, one of ordinary skill in the artwould readily recognize that a variety of pharmaceutically acceptablesalts, esters, amides, and prodrugs of a parent compound also could beincorporated into a composition, method, or article of manufacture ofthe present invention.

Suitable pharmaceutically acceptable basic addition salts include, butare not limited to cations based on alkali metals or alkaline earthmetals such as lithium, sodium, potassium, calcium, magnesium andaluminum salts and the like and nontoxic quaternary ammonia and aminecations including ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine,ethylamine and the like. Other representative organic amines useful forthe formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine and the like.

Other possible compounds include pharmaceutically acceptable amides andesters. For a description of pharmaceutically acceptable esters asprodrugs, see Bundgaard, E., ed., (1985) Design of Prodrugs, ElsevierScience Publishers, Amsterdam, which is hereby incorporated byreference. These esters are typically formed from the correspondingcarboxylic acid and an alcohol. Generally, ester formation can beaccomplished via conventional synthetic techniques. (See, e.g., MarchAdvanced Organic Chemistry, 3rd Ed., John Wiley & Sons, New York p. 1157(1985) and references cited therein, and Mark et al. Encyclopedia ofChemical Technology, John Wiley & Sons, New York (1980), both of whichare hereby incorporated by reference. The alcohol component of the esterwill generally comprise (i) a C2-C12 aliphatic alcohol that can or cannot contain one or more double bonds and can or can not contain branchedcarbons or (ii) a C7-C12 aromatic or heteroaromatic alcohols. Thisinvention also contemplates the use of those compositions, which areboth esters as described herein, and at the same time are thepharmaceutically acceptable salts thereof.

For a description of pharmaceutically acceptable amides as prodrugs, seeBundgaard, H., Ed., (1985) Design of Prodrugs, Elsevier SciencePublishers, Amsterdam. These amides are typically formed from thecorresponding carboxylic acid and an amine. Generally, amide formationcan be accomplished via conventional synthetic techniques. (See, e.g.,Advanced Organic Chemistry, 3rd Ed., John Wiley & Sons, New York, p.1152 (1985) and Mark et al. Encyclopedia of Chemical Technology, JohnWiley & Sons, New York (1980), both of which are hereby incorporated byreference. This invention also contemplates the use of thosecompositions, which are amides, as described herein, and at the sametime are the pharmaceutically acceptable salts thereof.

It also will be readily apparent to one with skill in the art that thecompounds can be generated in vivo by administration of a drug precursorwhich, following administration, releases the drug in vivo via achemical or physiological process (e.g., a parent compound on beingbrought to the physiological pH or through enzyme action is converted tothe desired drug form).

Administration

As noted above, it has been discovered that pain can be treated byconcurrently administering to a patient (e.g., a mammal, such as ahuman) in need thereof, an α4β2 PAM and an α4β2 receptor ligand. Suchcombination may be especially useful in expanding the dosage range forobtaining therapeutically beneficial effects.

The dosage range at which the α4β2 PAM and an α4β2 receptor ligand willbe administered concurrently can vary widely. The specific dosage willbe chosen by the patient's physician taking into account the particularcompounds chosen, the severity of the patient's illness, any othermedical conditions or diseases the patient is suffering from, otherdrugs the patient is taking and their potential to cause an interactionor adverse event, the patient's previous response to medication, andother factors. Suitable dosage ranges for the α4β2 PAM are from about0.0001 mg/kg to 100 mg/kg of body weight. Suitable dosage ranges for theα4β2 receptor ligand are from about 0.0001 mg/kg to 100 mg/kg of bodyweight.

The α4β2 PAM and an α4β2 receptor ligand should be administeredconcurrently in amounts that are effective to treat the patient's pain,cognitive disorder, or related condition. In more general terms, onewould create a combination of the present invention by choosing a dosageof an α4β2 PAM and an α4β2 receptor ligand according to the spirit ofthe guidelines presented above.

The invention also is carried out by administering an α4β2 PAM togetherwith an α4β2 receptor ligand in any manner which provides effectivelevels of the compounds in the body at the same time. Typically, thecombination will be administered orally.

However, the invention is not limited to oral administration. Theinvention should be construed to cover any route of administration thatis appropriate for the medications involved and for the patient. Forexample, transdermal administration may be very desirable for patientswho are forgetful or petulant about taking oral medicine. Injections maybe appropriate for patients refusing their medication. One of the drugsmay be administered by one route, such as oral, and the others may beadministered by the transdermal, percutaneous, intravenous,intramuscular, intranasal, or intrarectal route, in particularcircumstances. The route of administration may be varied in any way,limited by the physical properties of the drugs and the convenience ofthe patient and the caregiver.

Based on the diversity of the mechanisms underlying chronic pain (e.g.nociceptive or neuropathic, degrees of pain intensity, variousetiologies etc), currently available pain medications are notefficacious in all patients or in all pain conditions. Analgesics can bebroadly categorized as non-opioid analgesics (acetaminophen andnon-steroidal anti-inflammatory drugs (NSAIDs)), opioid analgesics(morphine) and adjuvant analgesics or co-analgesics (antiepileptic drugsand antidepressants). In a simplified classification, non-opioidanalgesics are mostly used to relieve mild to moderate nociceptive pain,adjuvant analgesics (gabapentin, pregabalin) are used to relieveneuropathic pain, and opioid analgesics are used to treat severe pain ofall origins, depending on the dose prescribed.

Nicotinic acetylcholine receptor ligands act at multiple locationsthroughout the pain pathway to relieve pain. Nicotinic acetylcholinereceptor ligands are found on primary sensory neurons (periphery) wherenociceptive information is initiated, in the cell body regions of theseneurons (i.e. the dorsal root ganglion or DRG), the dorsal spinal cordwhere the first pain synapse is located, in the brainstem cell bodyregions that control descending innervation, as well as in the higherbrain regions that integrate and perceive sensory information such asthe thalamus and the cortex. The current theory supported by evidencefrom multiple sources (reviewed in Decker et al., Curr Topics Med Chem,4: 369, 2004) is that anti-nociceptive effects of nAChR ligands aremediated by activation of brain stem nuclei with descending inhibitoryinputs to the spinal cord. Additional pathways may also mediateanalgesic effects of nAChR agonists in persistent or neuropathic pain.

Another aspect of the invention is the potential to enhance efficacy ofother medications used for treating pain when combined with an α4β2 PAM.As noted above, examples of currently used drugs include opioids,gabapentin, pregabalin, duloxetine and others. Novel mechanisms such ascannabinoids, vanilloid receptor antagonists, calcium channel blockersand sodium channel blockers are also being developed for the treatmentof pain. For many of these mechanisms, it is emerging that a componentof efficacy may be driven by activation of descending inhibitory inputs.For example, opioid analgesics can block pain transmission, in part byincreasing descending inhibitory pathways to modulate pain transmissionat the spinal level (Pasternack, G. W., Clin Neuropharmcol. 16: 1, 1993;Lauretti, G. T., Expert Reviews in Neurotherapeutics, 6: 613-622. 2006).Since these drugs exert their effect via activating descendinginhibitory inputs, and these pathways can be shared or commonlyactivated by α4β2 nAChR ligands, it is anticipated thatco-administration of α4β2 selective PAMs can lead to enhanced efficacyof other analgesic agents by amplifying the descending inhibitorycontrol of spinal cord activation. Thus, combination with α4β2 PAMsenables the opportunity to create analgesic medications with either abroader or superior spectrum of efficacy that would improve thetreatment of chronic pain.

Other nAChR-mediated diseases or disorders also can benefit from suchconcurrent administration. The combination of α4β2 nAChR ligands andα4β2 selective PAMs can be used for treatment of diseases or disordersrelated to the cholinergic system of the central nervous system, theperipheral nervous system, diseases or disorders related to smoothmuscle contraction, endocrine diseases or disorders, diseases ordisorders related to neuro-degeneration, diseases or disorders relatedto inflammation, and withdrawal symptoms caused by the termination ofabuse of chemical substances, in for example nicotine, as well as pain.In a particular embodiment, the combination is useful for conditions anddisorders related to attention deficit disorder, attention deficithyperactivity disorder (ADHD), Alzheimer's disease (AD), schizophrenia,mild cognitive impairment, age-associated memory impairment (AAMI),senile dementia, AIDS dementia, Pick's Disease, dementia associated withLewy bodies, dementia associated with Down's syndrome, schizophrenia,smoking cessation, substance abuse, amyotrophic lateral sclerosis,Huntington's disease, diminished CNS function associated with traumaticbrain injury, acute pain, post-surgical pain, chronic pain, inflammatorypain, neuropathic pain, infertility, lack of circulation, need for newblood vessel growth associated with wound healing, more particularlycirculation around a vascular occlusion, need for new blood vesselgrowth associated with vascularization of skin grafts, ischemia,inflammation, sepsis, wound healing, and other complications associatedwith diabetes, among other systemic and neuroimmunomodulatoryactivities. The method is useful for conditions and disorders related toconditions and disorders characterized by neuropyschological andcognitive dysfunction, for example in Alzheimer's disease, bipolardisorder, schizophrenia, schizoaffective disorder, and other relateddisorders characterized by neuropyschological and cognitive dysfunction,in particular.

For example, one embodiment relates to a method of use for treating orpreventing a condition or disorder characterized by attention orcognitive dysfunction, such as Alzhimer's disease and ADHD, among othercondition and disorders. The method comprises the step of administeringa therapeutically effective amount of a nicotinic acetylcholine receptorsubtype α4β2 positive allosteric modulator to a subject in need thereofin combination with a drug that improves cholinergic function. Examplesof such drugs are nicotinic acetylcholine receptor ligands andacetylcholinesterase inhibitors.

Another method of use relates to treating or preventing a condition ordisorder characterized by neuropyschological dysfunction, for exampleschizophrenia, wherein the method comprises the step of administering atherapeutically effective amount of a nicotinic acetylcholine receptorsubtype α4β2 positive allosteric modulator to a subject in need thereofin combination with an antipsychotic agent.

Biological Activity EXAMPLE A α4β2 Positive Allosteric ModulatorEnhances the Effects of Nicotinic Agonists

Calcium Flux Assays Using Cells Expressing nAChR Subtypes

Experimental Procedure: Human embryonic kidney (HEK) 293 cells stablyexpressing human α4β2 or α3β4 combinations are grown to confluency in162 cm² tissue culture flasks in DMEM media supplemented with 10% FBSand 25 μg/ml zeocin and 200 μg/ml hygromycin B. IMR-32 neuroblastomacells (ATCC) are grown to confluency in 162 cm² tissue culture flasks inminimum essential media supplemented with 10% FBS and 1 mM sodiumpyruvate, 1% non-essential amino acids and 1% antibiotic-antimycotic.The cells are then dissociated using cell dissociation buffer and100-150 μl per well of 3.5×10⁵ cells/ml cell suspension (˜50,000-100,000cells/well) was plated into 96-well black plates (poly-D-lysineprecoated) with clear bottom and maintained for 24-48 hours in a tissueculture incubator at 37° C. under an atmosphere of 5% CO₂: 95% air.Other clonal cell lines or primary cell cultures that express endogenousα4* nicotinic receptors may also be used in this assay. Calcium flux wasmeasured using calcium-3 assay kit (Molecular Devices, Sunnyvale,Calif.) or fluo-4 (Invitrogen). A stock solution of the dye was preparedby dissolving each vial supplied by the vendor in Hank's balanced saltsolution buffer (HBSS) or 150 mM NMDG, 20 mM CaCl₂ containing 10 mMHEPES, The stock solution was diluted 1:20 using the same buffer beforeuse. The growth media was removed from the cells. The cells were loadedwith 100 μl of the dye per well and incubated at room temperature for upto one hour for HEK 293 clonal stable cell lines or 30 minutes-45minutes at 37° C. for IMR-32 cells Fluorescence measurements were readsimultaneously from all the wells by a Fluorometic Imaging Plate Reader(FLIPR) at an excitation wavelength of 480 nm and an emission wavelengthof 520 nm. Baseline fluorescence was measured for the first 6 seconds atwhich 3× concentrations of modulator/test compounds were added to thecell plate at 50 μl and incubated for five minutes. The fluorescenceintensity was captured every second for the first 1 minute followed byevery 5 seconds for an additional 4 minutes. This procedure was followedby 50 μl of 4× concentration of agonist and readings were taken for aperiod of 3-5 minutes as described above. Data was normalized to maximalresponses and plotted as a function of concentration. The concentrationdependence of changes fluorescence responses was fitted by nonlinearregression analysis (GraphPad Prism, San Diego, Calif.) to obtain EC₅₀values.

The positive allosteric modulator effects on α4β2 nAChRs exemplified by3-(3-pyridin-3-yl-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1) and3,5-di(pyridin-3-yl)-1,2,4-oxadiazole (Compound 2) can be identified bymeasuring their potentiating effect to fluorescence changes inintracellular calcium using a fluorimetric plate reader. Thepotentiating effect of an α4β2 modulator on α4β2 receptor can also beillustrated by concentration responses to α4β2 agonists, for example5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine (Compound A) and(3R)-1-pyridin-3-ylpyrrolidin-3-amine (Compound B), in presence of afixed concentration of PAM. As shown in FIGS. 1A and 2A, in the presenceof an α4β2 PAM (for example,3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1) at 10μM), the concentration-responses to α4β2 agonists, for example5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine (Compound A) and(3R)-1-pyridin-3-ylpyrrolidin-3-amine (Compound B), are shiftedtypically by 1-2 log units (10-100-fold) to the left resulting in morepotent EC₅₀ values to agonists. In addition to compound A and B, otherknown nicotinic agonists can be left-shifted in presence of α4β2 PAMsuch as 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound1, FIG. 2C). When these experiments are done with cells expressing othernAChR subunits such as α3β4 (see FIGS. 1B and 2B), the PAM is unable toaffect the concentration responses to the agonists. This shows that PAMscan selective enhance potency of the compound selectively at α4β2, butnot other (e.g. α3β4) subtypes. This could lead to preferential effectsof the agonist at the desired subtype, viz., α4β2, without effects atother nicotinic receptor subtypes and thus enhancing in vivo selectivityof the agonist.

Table 1 lists the results for the compounds of the present invention.The activity (allosteric effects—potentiation of fluorescence responses)ranges are defined as follows; “a” denotes as activity range from200-400%, “b” denotes an activity range from 150-200%, “c” denotes anactivity range from 120-150% and “d” denotes an activity range 90-120%.

TABLE 1 Examples of Selected α4β2 positive allosteric modulators Exam-ple No. Structure Activity 1

a 2

a 3

a 4

b 5

c 7

b 9

d 10

a 19

b 35

a 40

a 41

c 42

c 52

d 55

c 68

b 11

a 125

a 101

a 76

b 83

a 132

a

EXAMPLE B α4β2 Positive Allosteric Modulator Enhances the Effects ofNicotinic Ligands with Very Low Intrinsic Agonist Efficacy

Calcium Flux Assays: HEK-293 cells stably expressing human α4β2 or α3β4are to confluency in 162 cm² tissue culture flasks in DMEM mediasupplemented with 10% FBS and 25 μg/ml zeocin and 200 μg/ml hygromycinB. IMR-32 neuroblastoma cells (ATCC) are grown to confluency in 162 cm²tissue culture flasks in minimum essential media supplemented with 10%FBS and 1 mM sodium pyruvate, 1% non-essential amino acids and 1%antibiotic-antimycotic. The cells are then dissociated using celldissociation buffer and 100-150 μl per well of 3.5×10⁵ cells/ml cellsuspension (˜50,000-100,000 cells/well) was plated into 96-well blackplates (poly-D-lysine precoated) with clear bottom and maintained for24-48 hours in a tissue culture incubator at 37° C. under an atmosphereof 5% CO₂: 95% air. Other clonal cell lines or dissociated primarycortical neurons that express endogenous α4* nicotinic receptors mayalso be used in this assay. Calcium flux was measured using calcium-3assay kit (Molecular Devices, Sunnyvale, Calif.) or fluo-4 (Invitrogen).A stock solution of the dye was prepared by dissolving each vialsupplied by the vendor in Hank's balanced salt solution buffer (HBSS) or150 mM NMDG, 20 mM CaCl₂ containing 10 mM HEPES. The stock solution wasdiluted 1:20 using the same buffer before use. The growth media wasremoved from the cells. The cells were loaded with 100 μl of the dye perwell and incubated at room temperature for up to one hour for HEK 293clonal stable cell lines or 30 minutes-45 minutes at 37° C. for IMR-32cells. Fluorescence measurements were read simultaneously from all thewells by a Fluorometic Imaging Plate Reader (FLIPR) at an excitationwavelength of 480 nm and an emission wavelength of 520 nm. Baselinefluorescence was measured for the first 6 seconds at which 3×concentrations of modulator/test compounds were added to the cell plateat 50 μl and incubated for five minutes. The fluorescence intensity wascaptured every second for the first 1 minute followed by every 5 secondsfor an additional 4 minutes. This procedure was followed by 50 μl of 4×concentration of agonist and readings were taken for a period of 3-5minutes as described above. Data was normalized to maximal responses andplotted as a function of concentration. The concentration dependence ofchanges fluorescence responses was fitted by nonlinear regressionanalysis (GraphPad Prism, San Diego, Calif.) to obtain EC₅₀ values.

α4β2 PAMs can also enhance the efficacy of partial agonists (compoundsthat bind, but activate α4β2 nAChRs with low intrinsic efficacy leadingto otherwise barely detectable effects on calcium responses). Forexample, responses to 2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine(Compound C) in the presence and absence of PAM is shown in FIG. 3. Theresults show in the presence of an α4β2 PAM (for example,3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1)), themaximum fluorescence calcium signal was substantially enhanced toapplication of 2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine at theα4β2 receptor (FIG. 3A), but again, not at the α3β4 receptor (FIG. 3B).Another example is provided by Compound D,(1S,5S)-3-(3,6-diaza-bicyclo[3.2.0]hept-3-yl)-quinoline; compound withtoluene-4-sulfonic acid which also binds to α4β2 nAChR ([³H]cyt Ki=6nM), but does not show substantial calcium responses alone; however,when co-incubated with α4β2 PAM, responses are substantially enhanced atα4β2 nAChR (FIG. 4A), but not at α3β4 nAChRs (FIG. 4B). Theseobservations provides mechanistic support for compounds like2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine and(1S,5S)-3-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)-quinoline being moreeffective when co-applied with the PAM. The potentiation of α4β2 effectsby PAM may potential for optimizing and enhancing efficacy inindications such as ADHD, cognitive deficits, Alzheimer's disease, andpain.

FIG. 5 shows a comparison of EC₅₀ values from calcium fluorescence(FLIPR) assays using α4β2 nAChRs of several nicotinic agonists includingvarenicline and ispronicline in the presence and absence of positiveallosteric modulator. The potency (EC₅₀ values) of the nicotinicagonists increase in the presence of the positive allosteric modulator.

EXAMPLE C α4β2 PAM Enhances the Efficacy of Compound A in an In VivoModel of Neuropathic Pain

To assess whether α4β2 PAM can increase antinociceptive responses ofagonists in vivo, the following study was conducted. The materials andmethods used to accomplish the study follow.

Animals: Male Sprague-Dawley rats (Charles River, Wilmington, Mass.)weighing 120-150 grams at time of surgery were utilized. These animalswere group housed in AAALAC approved facilities at Abbott Laboratoriesin a temperature-regulated environment with lights on between 0700 and2000 hours. Food and water was available ad libitum except duringtesting. All animal handling and experimental protocols were approved byan institutional animal care and use committee (IACUC). All experimentswere performed during the light cycle.

Chemicals: 5-[(2R)-Azetidin-2-ylmethoxy]-2-chloropyridine (Compound A,1-100 nmol/kg) and 3-(3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile(α4β2 PAM Compound 1, 1-35 μmol/kg, i.p.) was used. Compound A and D wasprepared in saline and injected in solution in a volume of 2 ml/kg bodyweight 30 minutes before behavioral evaluation. Compound1,3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile, was prepared in30% hydroxybetacyclodextrin and injected in solution in a volume of 4ml/kg body weight immediately before Compound A. For studies withCompound D, the doses tested ranged from 0.3-30 μmol/kg i.p.

Experimental Procedure: To produce neuropathic pain, tight ligation ofthe L5-L6 spinal nerves was performed. As previously described in detailby Kim and Chung (Kim S H and Chung J M (1992), Pain 50: 355), followingsterilization procedures, a 1.5 cm incision was made dorsal to thelumbosacral plexus. The paraspinal muscles (left side) were separatedfrom the spinous processes, the L5 and L6 spinal nerves isolated, andtightly ligated with 3-0 silk thread. Following hemostasis, the woundwas sutured and coated with antibiotic ointment. The rats were allowedto recover and then placed in a cage with soft bedding for 7-14 daysbefore behavioral testing for mechanical allodynia.

Tactile allodynia was measured using calibrated (force; g) von Freyfilaments (Stoelting, Wood Dale, Ill.). Briefly, rats were placed intoindividual plexiglass containers and allowed to acclimate for 15-20minutes before testing. Withdrawal threshold was determined byincreasing and decreasing stimulus intensity and estimated using a Dixonnon-parametric test (Chaplan et al., 1994; Chaplan S R, Bach F W, PogrelJ W, Chung J M and Yaksh T L (1994) J Neurosci Methods 53:55-63). Onlyrats with threshold scores ≦4.5 g were considered allodynic and utilizedin further testing. A percent of maximal possible effect (% M.P.E.) ofthe tested compounds was calculated according to the formula:([post-drug threshold]−[baseline threshold])/([maximumthreshold]−[baseline threshold])×100%, where maximum threshold was equalto 15 g.

Statistical analysis: Analysis of the in vivo data was carried out usinganalysis of variance. Where appropriate, Bonferroni's MultipleComparison Test was used for post-hoc analysis. The level ofsignificance was set at p less than 0.05. Data are presented as mean±S.E.M.

Results: As shown in FIG. 6A, tight ligation of L5-L6 spinal nervesinduced pronounced mechanical allodynia with a decrease in mechanicalpaw withdrawal threshold (PWT) in the vehicle group to 2.6±0.4 g.Compound 1,3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (PAM,10 mg/kg, i.p.) did not produce significant reversal of nerve injuryinduced mechanical allodynia (PWT: 3.3±0.4 g, P greater than 0.05 vs.vehicle group). Compound A (0.03 μmol/kg, i.p.) produced weak butsignificant reversal of mechanical allodynia (PWT: 5.6±0.3 g, P lessthan 0.001 vs. vehicle group). When co-administered, CompoundA+3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1,PAM) produced a pronounced reversal of nerve injury-induced mechanicalallodynia (PWT: 12.1±0.5 g) that was significantly different fromvehicle (P less than 0.001), but also from Compound A alone (P less than0.001) and 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile,Compound 1, alone (P less than 0.001). This study demonstrates that theco-administration of a α4β2 positive allosteric modulator to a α4β2agonist potentiate the antiallodynic effects of the agonist. Since theefficacy of the α4β2 ligand in neuropathic pain is robustly improved inpresence of a PAM, an overall improvement in therapeutic window for thetreatment of pain may be envisaged utilizing a combination approach(agonist in combination with the α4β2 PAM).

FIG. 6B shows that the effects of PAM(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile, Compound 1) aredose-dependent. An ineffective dose of Compound A (1 nmol/kg), whencombined with varying doses of PAM(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile, Compound 1)results in dose-dependent increase in efficacy, approaching at leastthat of gabapentin, a drug clinically used for the treatment ofneuropathic pain.

FIG. 7A shows dose dependent effects in neuropathic pain of5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine (Compound A) alone, α4β2PAM (3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile, Compound 1)alone and a combination of Compound 1 (3.5 μmol/kg) with various dosesof Compound A. α4β2 PAM (Compound 1) alone is ineffective, but iscapable of left-shifting the dose response curve of Compound A in theChung model of neuropathic pain.

EXAMPLE D Analysis of Compound Effects on Emesis in Ferrets

Fasted male ferrets (Marshall BioResources, North Rose, N.Y.) weighingbetween 1.0 and 1.7 kg are used to determine the emetic effects. α4β2PAM (Compound 1) was administered first and thirty minutes later,Compound A was administered at various doses. After dosing, the animalswere observed for emesis and behaviors characteristic of nausea for aperiod of 90 minutes. The percentage of animals that experienced emesisat a given dose was recorded.

FIG. 7B shows effects on emesis. Shown are effects of5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine (Compound A) alone, α4β2PAM (Compound 1) alone and a combination of Compound 1 (3.5 μmol/kg)with various doses of compound A. α4β2 PAM (Compound 1) alone does notcause emesis, and does not shift the dose response curve of Compound Ain the ferret model of emesis.

FIGS. 8A and 8B show plasma level analysis in models of neuropathic painand emesis. Note the left ward shift in efficacy of Compound A in FIG.8A, but no shift in effects on emesis in FIG. 8B. In other words,maximal efficacy of Compound A can be realized in neuropathic painwithout incidence of emesis, in presence of α4β2 PAM (Compound 1), thuswidening the therapeutic window of α4β2 nAChR agonists

EXAMPLE E α4β2 Partial Agonists can be Effective in ReversingNeuropathic Pain in the Presence of α4β2 Positive Allosteric Modulators

To further examine effects in neuropathic pain, the effects of CompoundD, another α4β2 ligand with low intrinsic efficacy (partial agonist) wasexamined in the Chung model. Alone, Compound D is ineffective inreversing neuropathic pain, but when combined with the PAM (Compound 1),significant efficacy can be realized. FIG. 9 shows the efficacy ofpartial agonist, Compound D in the presence and absence of α4β2 PAM(Compound 1). Compound D when administered alone is ineffective inrelieving pain. When co-dosed with α4β2 PAM (Compound 1), Compound D isnow effective, and shows significant relief of neuropathic pain in rats.As shown previously, PAM (Compound 1) alone is ineffective (P+V).

Characterization of Nicotinic Acetylcholine Receptor Ligands

In addition to the assays previously described for assessing nicotinicacetylcholine receptor positive allosteric modulators(fluorescence-based measurements, electrophysiology measurements usingXenopus oocytes or cell lines), the receptor interactions of positiveallosteric modulators at α4β2 nAChRs also can be evaluated according tothe [³H]-POB binding assay, which was performed as described below.

[³H]-3-(5-(Pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile ([³H]-POB)Binding

[³H]-POB ([³H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile)binding to a α4β2 nAChR modulator site was determined using membraneenriched fractions from human cortex (ABS Inc., Wilmington, Del.).Pellets were thawed at 4° C., washed and resuspended with a Polytron ata setting of 7 in 30 volumes of BSS-Tris buffer (120 mM NaCl, 5 mM KCl,2 mM CaCl₂, 2 mM MgCl₂, and 50 mM Tris-Cl, pH 7.4, 4° C.). Forsaturation binding isotherms, eight concentrations of [³H]-POB (10-250nM) in quadruplicate and homogenate containing 100-200 μg of proteinwere incubated in a final volume of 500 μL for 75 minutes at 4° C.Non-specific binding was determined in the presence of 30 μM unlabeled3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile. Under theseconditions, saturable binding of [³H]-POB binding was measured inmembrane enriched fractions from human frontal cortex (FIG. 10). TheK_(d) and B_(max) values were 60±16 nM and 2900±500 fmol/mg protein,respectively. Membrane preparations from other species (rat, mouse,ferret) and from clonal or transfected cell lines that express α4β2nAChRs cloned from various species may also be used in this bindingassay.

For use in concentration-inhibition assays, seven log-dilutionconcentrations of test compounds containing 100-200 μg of protein, and50 nM [³H]-POB (16.4 Ci/mmol) were incubated in a final volume of 500 μLfor 75 minutes at 4° C. in duplicate. Non-specific binding wasdetermined in the presence of 30 μM3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile. Boundradioactivity was collected on Millipore MultiScreen® harvest plates FBpresoaked with 0.3% polyethyleneimine using a PerkinElmer cellharvester, washed with 2.5 mL of ice-cold buffer, and radioactivity wasdetermined using a PerkinElmer TopCount Microplate beta counter.Dissociation constant (K_(d)) and maximum binding (B_(max)) values fromsaturation binding experiments were determined using GraphPad Prism(Graphpad Software, San Diego, Calif.). IC₅₀ values were determined bynonlinear regression in Microsoft® Excel or Assay Explorer. K_(i) valueswere calculated from the IC₅₀s using the Cheng-Prusoff equation, whereK_(i)=IC₅₀/(1+[Ligand]/K_(D)]).

[³H]-POB was obtained according to the preparation procedures generallydescribed in Example 135 shown below.

EXAMPLE 135 [³H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrileEXAMPLE 135A3-(5-(5-bromopyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile

The title compound was prepared according to the procedure of Example 4Busing 3-cyano-N′-hydroxybenzimidamide and 5-bromonicotinoyl chloride(Alfa). ¹H NMR (300 MHz, DMSO-d₆) δ 7.67 (m, 1H), 7.74 (m, 1H), 8.41 (m,1H), 8.49 (m, 1H), 8.64 (s, 1H), 8.93 (s, 1H), 9.4 (s, 1H) ppm; MS(DCI/NH₃) m/z 327 (M+H)⁺.

EXAMPLE 135B [³H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile([³H]-POB)

The compound of Example 135A was dissolved in a mixture ofdichloromethane, triethylamine, and 5% palladium on carbon. The reactionsolution was then saturated with tritium gas (1.2 Ci). The reactionmixture was stirred at room temperature for 3.5 hours, the catalyst wasremoved by filtration, ant the filtrate was concentrated to yield crudetritiated product. Further purification of the crude material byreverse-phase HPLC using a 30 minute 40% isocratic acetonitrile run(column LunaC18, 254 nm) to provide a total of 200 mCi (1 mL, methanol).

The radiochemical purity of [³H]-POB was found to be 99% and thespecific activity was determined to be 16.4 Ci/mmol.

Nicotinic acetylcholine receptor ligands suitable for the inventionexhibit K_(i) values ranging about 1 nanomolar to about 10 micromolarwhen tested by the [³H]-POB assay, many having a K_(i) of less than 5micromolar. Compounds that modulate the function of α4β2 nAChRs byaltering the activity of the receptor or signaling are suitable for thecomposition. More specifically, the compounds that function asallosteric modulators enhancing the efficacy and/or potency ofacetylcholine or a nicotinic agonist are desired. Multiple binding sitesat α4β2 nAChRs may exist for such compounds, of which only one site maybe defined by [³H]POB binding.

Also contemplated is compound of formula (II*):

wherein Ar² is aryl or heteroaryl, wherein the aryl or heteroaryl issubstituted or unsubstituted, and, when substituted, the aryl orheteroaryl is substituted with 1, 2, 3, or 4 substituents selected fromhalo, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₄-C₇ cycloalkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₅-C₁₀ heteroaryl, C₄-C₁₀ heterocycle, C₁-C₆ alkyl,—(C₁-C₆ alkyl)NHC(O)O—(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆alkylcarbonyl, amino, hydroxyl, haloalkyl-C(O)—, haloalkyl-SO₂—,alkyl-SO₂—, —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, cyano,nitro, C₁-C₆ acylamino, C₁-C₆ alkoxy, —C(O)NH₂, —C(O)O—(C₁-C₆ alkyl),and carboxy; and

Ar³ is aryl or heteroaryl, wherein the aryl or heteroaryl is substitutedor unsubstituted, and, when substituted, the aryl or heteroaryl issubstituted with a substituent selected from halo, C₁-C₆ haloalkyl,C₆-C₁₀ aryl, C₄-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₅-C₁₀heteroaryl, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, amino, hydroxyl,haloalkyl-SO₂—, cyano, nitro, C₁-C₆ acylamino, C₁-C₆ alkoxy, —N(C₁-C₆alkyl)₂, and carboxy; wherein at least one of the available atoms withina compound of formula (II*) is replaced with a radioisotope. Aparticular radiolabelled compound of formula (II*) is[³H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile. Suchcompounds are suitable for use in determining the binding affinity ofnicotinic acetylcholine receptor subtype α4β2 positive allostericmodulators.

Another embodiment of the invention is a radiolabeled compound offormula (II*), wherein Ar² and Ar³ are independently phenyl, pyrazinyl,pyridinyl, pyrimidinyl, pyridazine, triazinyl, or a bicyclic heteroaryl,substituted independently with 0, 1, 2, 3, or 4 substitutents selectedfrom the group consisting of alkoxy, alkoxycarbonyl,alkoxycarbonylamino, alkoxycarbonylaminoalkyl, alkyl, alkylamino,alkylcarbonyl, alkylsulfonyl, amido, amino, aminoalkyl, carboxy,dialkylamino, dialkylaminoalkyl, halo, haloalkyl, haloalkylcarbonyl,heteroaryl, heterocycle, hydroxy, hydroxyalkyl, cyano, nitro,sulfonamide and dialkylsulfonylformimidamide; provided that when one ofAr² and Ar³ is pyridinyl or aryl, the other is not pyridinyl; when Ar³is pyridinyl, Ar² is not pyrazinyl.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. The compositions, methods,and articles of manufacture have been described with reference tovarious specific embodiments and techniques. However, various changesand modifications, including without limitation those relating to thecompounds, substituents, syntheses, and/or methods of use of theinvention, may be made without departing from the spirit and scopethereof. The examples described herein are intended only to illustrateand do not limit the scope of the invention as defined in the appendedclaims and equivalents thereof.

1. A compound of formula (II):

wherein Ar² and Ar³ are independently, optionally substituted aryl orheteroaryl.
 2. A compound of formula (II):

wherein Ar² and Ar³ are independently aryl, pyrazinyl, pyridazinyl,pyridinyl, pyrimidinyl, triazinyl, or bicyclic heteroaryl, substitutedindependently with 0, 1, 2, 3, or 4 substitutents selected from thegroup consisting of alkoxy, alkoxycarbonyl, alkoxycarbonylamino,alkoxycarbonylaminoalkyl, alkyl, alkylamino, alkylcarbonyl,alkylsulfonyl, amido, amino, aminoalkyl, carboxy, dialkylamino,dialkylaminoalkyl, halo, haloalkyl, haloalkylcarbonyl, heteroaryl,heterocycle, hydroxy, hydroxyalkyl, cyano, nitro, oxo, sulfonamide anddialkylsulfonylformimidamide; provided that when one of Ar² and Ar³ ispyridinyl or aryl, the other is not pyridinyl; when Ar³ is pyridinyl,Ar² is not pyrazinyl; or a pharmaceutically acceptable salt thereof. 3.The compound of claim 2 or a pharmaceutically acceptable salt thereof,wherein Ar² is phenyl.
 4. The compound of claim 2 or a pharmaceuticallyacceptable salt thereof, wherein Ar² is pyridinyl.
 5. The compound ofclaim 2 or a pharmaceutically acceptable salt thereof, wherein Ar² isbicyclic heteroaryl.
 6. The compound of claim 2 or a pharmaceuticallyacceptable salt thereof, wherein Ar³ is pyrimidinyl or pyridazinyl. 7.The compound of claim 2 or a pharmaceutically acceptable salt thereof,wherein Ar³ is bicyclic heteroaryl.
 8. The compound of claim 2 or apharmaceutically acceptable salt thereof, wherein Ar² and Ar³ areindependently phenyl, pyridazinyl, pyridinyl, pyrimidinyl, or bicyclicheteroaryl.
 9. A compound of claim 2, selected from the group consistingof: 5-(2,3-difluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;5-(pyridin-3-yl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;2-fluoro-N,N-dimethyl-4-(3-(pyrimidin-5-yl)-1,2,4-oxadiazol-5-yl)aniline;3-(3-(pyrimidin-5-yl)-1,2,4-oxadiazol-5-yl)benzonitrile;5-(3,4-difluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole;3-(pyridazin-4-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;N,N-dimethyl-N′-(4-(3-(pyrimidin-5-yl)-1,2,4-oxadiazol-5-yl)phenylsulfonyl)formimidamide;5-(4-fluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;5-(3-fluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;3-(pyrimidin-5-yl)-5-(3,4,5-trifluorophenyl)-1,2,4-oxadiazole;5-(2-chloropyridin-4-yl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;3-(Pyridin-3-yl)-5-(pyrimidin-5-yl)-1,2,4-oxadiazole;5-(Pyridazin-4-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;3-(3-(pyridazin-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile;5-(3-fluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole;3-(pyridazin-4-yl)-5-(3,4,5-trifluorophenyl)-1,2,4-oxadiazole;5-(3,5-difluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole;5-(4-fluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole;3-(pyridazin-4-yl)-5-(pyrimidin-5-yl)-1,2,4-oxadiazole;3-(pyridazin-4-yl)-5-(2,3,6-trifluorophenyl)-1,2,4-oxadiazole;3-(pyridazin-4-yl)-5-(2,3,4-trifluorophenyl)-1,2,4-oxadiazole;N,N-dimethyl-N′-(4-(3-(pyridazin-4-yl)-1,2,4-oxadiazol-5yl)phenylsulfonyl) formimidamide;5-(3,4-difluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;3-(3,4-difluorophenyl)-5-(pyrimidin-5-yl)-1,2,4-oxadiazole;3-(pyrimidin-5-yl)-5-(2,3,4-trifluorophenyl)-1,2,4-oxadiazole;3-(pyrimidin-5-yl)-5-(2,3,6-trifluorophenyl)-1,2,4-oxadiazole;3-(pyrimidin-5-yl)-5-(2,3,4,5-tetrafluorophenyl)-1,2,4-oxadiazole;5-(imidazo[1,5-a]pyridin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(1H-indol-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(2,7-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(2-methylbenzofuran-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(benzo[d][1,2,3]thiadiazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(1H-benzo[d]imidazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(benzo[d]thiazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;3-(pyridin-3-yl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,4-oxadiazole;5-(1H-indol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(benzofuran-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(1-methyl-1H-benzo[d]imidazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;3-(imidazo[1,2-a]pyridin-6-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;5-(6-chloropyridin-3-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-1,2,4-oxadiazole;5-(6-fluoropyridin-3-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-1,2,4-oxadiazole;5-(5-fluoropyridin-3-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-1,2,4-oxadiazole;5-(1H-indazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2(3H)-one;5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazole-2(3H)-thione;1,3-dimethyl-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one;6-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2(3H)-one;5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one;6-(3-(Pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2-amine;6-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazole;5-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzo[d]oxazol-2(3H)-one;5-(5-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzo[d]oxazol-2(3H)-one;and 55-(benzo[d][1,3]dioxol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; ora pharmaceutically acceptable salt thereof.
 10. The compound of claim 2,selected from the group consisting of5-(3-fluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole;5-(3,4-difluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole,3-(pyridazin-4-yl)-5-(3,4,5-trifluorophenyl)-1,2,4-oxadiazole;5-(3,5-difluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole;5-(4-fluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole;3-(pyridazin-4-yl)-5-(2,3,6-trifluorophenyl)-1,2,4-oxadiazole; and3-(pyridazin-4-yl)-5-(2,3,4-trifluorophenyl)-1,2,4-oxadiazole; or apharmaceutically acceptable salt thereof.
 11. The compound of claim 2,selected from the group consisting of5-(2-chloropyridin-4-yl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;5-(2,3-difluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;5-(3-fluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;3-(pyrimidin-5-yl)-5-(3,4,5-trifluorophenyl)-1,2,4-oxadiazole5-(4-fluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;5-(3,4-difluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;3-(pyrimidin-5-yl)-5-(2,3,4-trifluorophenyl)-1,2,4-oxadiazole;3-(pyrimidin-5-yl)-5-(2,3,6-trifluorophenyl)-1,2,4-oxadiazole; and3-(pyrimidin-5-yl)-5-(2,3,4,5-tetrafluorophenyl)-1,2,4-oxadiazole; or apharmaceutically acceptable salt thereof.
 12. The compound of claim 2,selected from the group consisting of5-(imidazo[1,5-a]pyridin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(1H-indol-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(2,7-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(2-methylbenzofuran-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(benzo[d][1,2,3]thiadiazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(1H-benzo[d]imidazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(benzo[d]thiazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;3-(pyridin-3-yl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,4-oxadiazole;5-(1H-indol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(benzofuran-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(1-methyl-1H-benzo[d]imidazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(1H-indazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2(3H)-one;5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazole-2(3H)-thione;1,3-dimethyl-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one;6-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2(3H)-one;5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one;6-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2-amine;6-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazole; and5-(benzo[d][1,3]dioxol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; or apharmaceutically acceptable salt thereof.
 13. The compound of claim 2,selected from the group consisting of3-(imidazo[1,2-a]pyridin-6-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;5-(6-chloropyridin-3-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-1,2,4-oxadiazole;5-(6-fluoropyridin-3-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-1,2,4-oxadiazole;5-(5-fluoropyridin-3-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-1,2,4-oxadiazole;5-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzo[d]oxazol-2(3H)-one; and5-(5-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzo[d]oxazol-2(3H)-one;or a pharmaceutically acceptable salt thereof.
 14. A radiolabeledcompound of formula (II*):

wherein Ar² and Ar³ are independently aryl, pyrazinyl, pyridazinyl,pyrimidinyl, triazinyl, or a bicyclic heteroaryl substitutedindependently with 0, 1, 2, 3, or 4 substitutents selected from thegroup consisting of alkoxy, alkoxycarbonyl, alkoxycarbonylamino,alkoxycarbonylaminoalkyl, alkyl, alkylamino, alkylcarbonyl,alkylsulfonyl, amido, amino, aminoalkyl, carboxy, dialkylamino,dialkylaminoalkyl, halo, haloalkyl, haloalkylcarbonyl, heteroaryl,heterocycle, hydroxy, hydroxyalkyl, cyano, nitro, sulfonamide anddialkylsulfonylformimidamide; provided that when one of Ar² and Ar³ ispyridinyl or aryl, the other is not pyridinyl; when Ar³ is pyridinyl,Ar² is not pyrazinyl; or a pharmaceutically acceptable salt thereof. 15.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 2, or a salt thereof, and apharmaceutically acceptable carrier or excipient.
 16. The composition ofclaim 15, further comprising a nicotinic acetylcholine receptor ligand.17. The composition of claim 16, wherein the nicotinic acetylcholinereceptor ligand is a nicotinic acetylcholine receptor subtype α4β2ligand demonstrating a Ki value that as measured by [3H]-cytisinebinding assay (Ki Cyt) of about 0.001 nanomolar to about 100 micromolar.18. The composition of claim 16, wherein the nicotinic acetylcholinereceptor ligand is a nicotinic acetylcholine receptor subtype α4β2agonist or partial agonist.
 19. A method for use in treating orpreventing pain in a patient, comprising: (i) administering atherapeutically effective amount of the compound of claim 2; and (ii)administering a pain medication comprising a compound selected from anopioid, gabapentin, pregabalin, duloxetine, a cannabinoid ligand, avaniolloid receptor antagonist, calcium channel blocker and a sodiumchannel blocker wherein a descending modulatory pathway that is sharedor commonly activated via the α4β2 nicotinic receptor mechanism isactivated.
 20. A method for treating or preventing attention deficitdisorder, attention deficit hyperactivity disorder (ADHD), Alzheimer'sdisease (AD), bipolar disorder, mild cognitive impairment,age-associated memory impairment (AAMI), senile dementia, AIDS dementia,Pick's disease, dementia associated with Lewy bodies, dementiaassociated with Down's syndrome, schizophrenia, schizoaffectivedisorder, smoking cessation, substance abuse including alcohol abuse,amyotrophic lateral sclerosis, Huntington's disease, diminished CNSfunction associated with traumatic brain injury, or pain, comprisingadministering a therapeutically effective amount of the compound ofclaim 2, or a salt thereof, to a subject in need thereof.